Substituted hydroxamic acids and uses thereof

ABSTRACT

This invention provides compounds of formula (I): 
     
       
         
         
             
             
         
       
     
     wherein X 1 , X 2 , R 1a , R 1b , R 1c , R 1d , n, and G have values as described in the specification, useful as inhibitors of HDAC6. The invention also provides pharmaceutical compositions comprising the compounds of the invention and methods of using the compositions in the treatment of proliferative, inflammatory, infectious, neurological or cardiovascular diseases or disorders.

PRIORITY CLAIM

This application claims the benefit under 35 U.S.C. §119(e) of U.S.Provisional Patent Application Ser. No. 61/323,082, filed Apr. 12, 2010,incorporated by reference in its entirety, and U.S. Provisional PatentApplication Ser. No. 61/426,156, filed Dec. 22, 2010, incorporated byreference in its entirety.

FIELD OF THE INVENTION

The invention relates to compounds and methods for the selectiveinhibition of HDAC6. The present invention relates to compounds usefulas HDAC6 inhibitors. The invention also provides pharmaceuticalcompositions comprising the compounds of the invention and methods ofusing the compositions in the treatment of various diseases.

BACKGROUND OF THE INVENTION

Histone deacetylase 6 (HDAC6) is a member of a family of amidohydrolasescommonly referred as histone or lysine deacetylases (HDACs or KDACs) asthey catalyze the removal of acetyl groups from the s-amino group oflysine residues from proteins. The family includes 18 enzymes which canbe divided in 3 main classes based on their sequence homology to yeastenzymes Rpd3 (Class I), Hda1 (Class II) and Sir2 (Class III). A fourthclass was defined with the finding of a distinct mammalian enzyme—HDAC11 (reviewed in Yang, et al., Nature Rev. Mol. Cell. Biol. 2008,9:206-218 and in Saunders and Verdin, Oncogene 2007, 26(37):5489-5504).Biochemically, Class I (HDAC1, 2, 3, 8) and Class II (HDAC4, 5, 6, 7, 9,10) and Class IV (HDAC11) are Zn²⁺-dependent enzymes, while Class III(SIRT1-7) are dependent on nicotinamide adenine dinucleotide (NAD⁺) foractivity. Unlike all other HDACs, HDAC6 resides primarily in thecytosol. It has 2 functional catalytic domains and a carboxy-terminalZn²⁺-finger ubiquitin binding domain that binds ubiquitinated misfoldedproteins (Kawaguchi et al., Cell 2003, 115(6):727-738), ubiquitin(Boyaullt et al., EMBO J. 2006, 25(14): 3357-3366), as well asubiquitin-like FAT10 modifier (Kalveram et al., J. Cell Sci. 2008,121(24):4079-4088). Known substrates of HDAC6 include cytoskeletalproteins α-tubulin and cortactin; β-catenin which forms part of adherensjunctions and anchors the actin cytoskeleton; the chaperone Hsp90; andthe redox regulatory proteins peroxiredoxin (Prx) I and Prx II (reviewedin Boyault et al., Oncogene 2007, 26(37):5468-5476; Matthias et al.,Cell Cycle 2008, 7(1):7-10; Li et al., J Biol. Chem. 2008,283(19):12686-12690; Parmigiani et al., Proc. Natl. Acad. Sci. USA 2009,105(28):9633-9638). Thus, HDAC6 mediates a wide range of cellularfunctions including microtubule-dependent trafficking and signaling,membrane remodeling and chemotactic motility, involvement in control ofcellular adhesion, ubiquitin level sensing, regulation of chaperonelevels and activity, and responses to oxidative stress. All of thesefunctions may be important in tumorigenesis, tumor growth and survivalas well as metastasis (Simms-Waldrip et al., Mol. Genet. Metabolism2008, 94(3):283-286; Rodriguez-Gonzalez et al., Cancer Res. 2008,68(8):2557-2560; Kapoor, Int. J. Cancer 2009, 124:509; Lee et al.,Cancer Res. 2008, 68(18):7561-7569). Recent studies have shown HDAC6 tobe important in autophagy, an alternative pathway for proteindegradation that compensates for deficiencies in the activity of theubiquitin proteasome system or expression of proteins prone to formaggregates and can be activated following treatment with a proteasomeinhibitor (Kawaguchi et al., Cell 2003, 115(6):727-738; Iwata et al., J.Biol. Chem. 2005, 280(48): 40282-40292; Ding et al., Am. J. Pathol.2007, 171:513-524, Pandey et al., Nature 2007, 447(7146):860-864).Although the molecular mechanistic details are not completelyunderstood, HDAC6 binds ubiquitinated or ubiquitin-like conjugatedmisfolded proteins which would otherwise induce proteotoxic stress andthen serves as an adaptor protein to traffic the ubiquitinated cargo tothe microtubule organizing center using the microtubule network via itsknown association with dynein motor protein. The resulting perinuclearaggregates, known as aggresomes, are then degraded by fusion withlysosomes in an HDAC6- and cortactin-dependent process which inducesremodeling of the actin cytoskeleton proximal to aggresomes (Lee et al.,EMBO J. 2010, 29:969-980). In addition, HDAC6 regulates a variety ofbiological processes dependent on its association with the microtubularnetwork including cellular adhesion (Tran et al., J. Cell Sci. 2007,120(8):1469-1479) and migration (Zhang et al., Mol. Cell. 2007,27(2):197-213; reviewed in Valenzuela-Fernandez et al., Trends Cell.Biol. 2008, 18(6):291-297), epithelial to mesenchymal transition (Shanet al., J. Biol. Chem. 2008, 283(30):21065-21073), resistance to anoikis(Lee et al., Cancer Res. 2008, 68(18):7561-7569), epithelial growthfactor-mediated Wnt signaling via β-catenin deacetylation (Li et al., J.Biol. Chem. 2008, 283(19):12686-12690) and epithelial growth factorreceptor stabilization by endocytic trafficking (Lissanu Deribe et al.,Sci. Signal. 2009, 2(102): ra84; Gao et al., J. Biol. Chem. 2010,285:11219-11226); all events that promote oncogenesis and metastasis(Lee et al., Cancer Res. 2008, 68(18):7561-7569). HDAC6 activity isknown to be upregulated by Aurora A kinase in cilia formation (Pugachevaet al., Cell 2007, 129(7):1351-1363) and indirectly by farnesyltransferase with which HDAC6 forms a complex with microtubules (Zhou etal., J. Biol. Chem. 2009, 284(15): 9648-9655). Also, HDAC6 is negativelyregulated by tau protein (Perez et al., J. Neurochem. 2009,109(6):1756-1766).

Diseases in which selective HDAC6 inhibition could have a potentialbenefit include cancer (reviewed in Simms-Waldrip et al., Mol. Genet.Metabolism 2008, 94(3):283-286 and Rodriguez-Gonzalez et al., CancerRes. 2008, 68(8):2557-2560), specifically: multiple myeloma (Hideshimaet al., Proc. Natl. Acad. Sci. USA 2005, 102(24):8567-8572); lung cancer(Kamemura et al., Biochem. Biophys. Res. Commun. 2008, 374(1):84-89);ovarian cancer (Bazzaro et al., Clin. Cancer Res. 2008,14(22):7340-7347); breast cancer (Lee et al., Cancer Res. 2008,68(18):7561-7569); prostate cancer (Mellado et al., Clin. Trans. Onco.2009, 11(1):5-10); pancreatic cancer (Nawrocki et al., Cancer Res. 2006,66(7):3773-3781); renal cancer (Cha et al., Clin. Cancer Res. 2009,15(3):840-850); and leukemias such as acute myeloid leukemia (AML)(Fiskus et al., Blood 2008, 112(7):2896-2905) and acute lymphoblasticleukemia (ALL) (Rodriguez-Gonzalez et al., Blood 2008, 112(11): Abstract1923).

Inhibition of HDAC6 may also have a role in cardiovascular disease, i.e.cardiovascular stress, including pressure overload, chronic ischemia,and infarction-reperfusion injury (Tannous et al., Circulation 2008,117(24):3070-3078); bacterial infection, including those caused byuropathogenic Escherichia coli (Dhakal and Mulve, J. Biol. Chem. 2008,284(1):446-454); neurological diseases caused by accumulation ofintracellular protein aggregates such as Huntington's disease (reviewedin Kazantsev et al., Nat. Rev. Drug Disc. 2008, 7(10):854-868; see alsoDompierre et al., J. Neurosci. 2007, 27(13):3571-3583; Kozikowski etal., J. Med. Chem. 2007, 50:3054-3061) or central nervous system traumacaused by tissue injury, oxidative-stress induced neuronal or axomaldegeneration (Rivieccio et al., Proc. Natl. Acad. Sci. USA 2009,106(46):19599-195604); and inflammation, including reduction ofpro-inflammatory cytokine IL-1β (Carta et al., Blood 2006,108(5):1618-1626), increased expression of the FOXP3 transcriptionfactor, which induces immunosuppressive function of regulatory T-cellsresulting in benefits in chronic diseases such as rheumatoid arthritis,psoriasis, multiple sclerosis, lupus and organ transplant rejection(reviewed in Wang et al., Nat. Rev. Drug Disc. 2009, 8(12):969-981).

Given the complex function of HDAC6, selective inhibitors could havepotential utility when used alone or in combination with otherchemotherapeutics such as microtubule destabilizing agents (Zhou et al.,J. Biol. Chem. 2009, 284(15): 9648-9655); Hsp90 inhibitors (Rao et al.,Blood 2008, 112(5)1886-1893); inhibitors of Hsp90 client proteins,including receptor tyrosine kinases such as Her-2 or VEGFR (Bhalla etal., J. Clin. Oncol. 2006, 24(18S): Abstract 1923; Park et al., Biochem.Biophys. Res. Commun. 2008, 368(2):318-322), and signaling kinases suchas Bcr-Abl, Akt, mutant FLT-3, c-Raf, and MEK (Bhalla et al., J. Clin.Oncol. 2006, 24(18S): Abstract 1923; Kamemura et al., Biochem. Biophys.Res. Commun. 2008, 374(1):84-89); inhibitors of cell cycle kinasesAurora A and Aurora B (Pugacheva et al., Cell 2007, 129(7):1351-1363;Park et al., J. Mol. Med. 2008, 86(1):117-128; Cha et al., Clin. CancerRes. 2009, 15(3):840-850); EGFR inhibitors (Lissanu Deribe et al., Sci.Signal. 2009, 2(102): ra84; Gao et al., J. Biol. Chem. 2010,285:11219-11226) and proteasome inhibitors (Hideshima et al., Proc.Natl. Acad. Sci. USA 2005, 102(24):8567-8572) or other inhibitors of theubiquitin proteasome system such as ubiquitin and ubiqutin-likeactivating (E1), conjugation (E2), ligase enzymes (E3, E4) anddeubiquitinase enzymes (DUBS) as well as modulators of autophagy andprotein homeostasis pathways. In addition, HDAC6 inhibitors could becombined with radiation therapy (Kim et al., Radiother. Oncol. 2009,92(1):125-132).

Clearly, it would be beneficial to provide novel HDAC6 inhibitors thatpossess good therapeutic properties, especially for the treatment ofproliferative diseases or disorders.

DETAILED DESCRIPTION OF THE INVENTION 1. General Description ofCompounds of the Invention

The present invention provides compounds that are effective inhibitorsof HDAC6. These compounds are useful for inhibiting HDAC6 activity invitro and in vivo, and are especially useful for the treatment ofvarious cell proliferative diseases or disorders. The compounds of theinvention are represented by formula (I):

or a pharmaceutically acceptable salt thereof;

wherein:

X₁ is CH or N;

X₂ is CH or N;

n is 1-2;

R^(1a) is hydrogen, fluoro, C₁₋₄ alkyl, or C₁₋₃-fluoroalkyl;

R^(1b) is hydrogen, fluoro, C₁₋₄ alkyl, or C₁₋₃-fluoroalkyl; or R^(1a)and R^(1b) are taken together to form an oxo group;

each occurrence of R^(1c) is independently hydrogen, fluoro, C₁₋₄ alkyl,or C₁₋₃-fluoroalkyl;

each occurrence of R^(1a) is independently hydrogen, fluoro, C₁₋₄ alkyl,or C₁₋₃-fluoroalkyl;

G is —R³, —V₁—R³, —V₁-L₁-R³, -L₂-V₁—R³, -L₂-V₂—R³, or -L₁-R³; or whenR^(1a) and R^(1b) are taken together to form an oxo group, G is —R³, or-L₁-R³;

L₁ is an unsubstituted or substituted C₁₋₃ alkylene chain;

L₂ is an unsubstituted or substituted C₂₋₃ alkylene chain;

V₁ is —C(O)—, —C(S)—, —C(O)—CR^(A)═CR^(A)—, —C(O)—N(R^(4a))—, —C(O)—O—,or —S(O)₂—;

V₂ is —N(R^(4a))—, —N(R^(4a))—C(O)—, —SO₂—N(R^(4a))—, —N(R^(4a))—SO₂—,—O—, —S—, —S(O)—,

N(R^(4a))—C(O)—N(R^(4a))—, —N(R^(4a))—C(O)—O—, —O—C(O)—N(R^(4a))—, or—N(R^(4a))—SO₂—N(R^(4a))—;

R³ is unsubstituted or substituted C₁₋₆ aliphatic, unsubstituted orsubstituted 3-10-membered cycloaliphatic, unsubstituted or substituted4-10-membered heterocyclyl having 1-4 heteroatoms independently selectedfrom nitrogen, oxygen, and sulfur, unsubstituted or substituted6-10-membered aryl, or unsubstituted or substituted 5-10-memberedheteroaryl having 1-5 heteroatoms independently selected from nitrogen,oxygen, and sulfur;

each occurrence of R^(A) is independently hydrogen, fluoro, orunsubstituted or substituted C₁₋₄ aliphatic; and

each occurrence of R^(4a) is independently hydrogen, or unsubstituted orsubstituted C₁₋₄ aliphatic;

provided that the compound of formula (I) is other thaw

-   N-hydroxy-5-(4-methoxybenzyl)-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2-carboxamide;    or-   N-hydroxy-5-(3-(trifluoromethyl)benzyl)-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2-carboxamide.

2. Compounds and Definitions

Compounds of this invention include those described generally forformula (I) above, and are further illustrated by the classes,subclasses, and species disclosed herein. As used herein, the followingdefinitions shall apply unless otherwise indicated.

As described herein, compounds of the invention may be optionallysubstituted with one or more substituents, such as are illustratedgenerally above, or as exemplified by particular classes, subclasses,and species of the invention. It will be appreciated that the phrase“optionally substituted” is used interchangeably with the phrase“substituted or unsubstituted.” In general, the term “substituted”,whether preceded by the term “optionally” or not, means that a hydrogenradical of the designated moiety is replaced with the radical of aspecified substituent, provided that the substitution results in astable or chemically feasible compound. The term “substitutable”, whenused in reference to a designated atom, means that attached to the atomis a hydrogen radical, which hydrogen atom can be replaced with theradical of a suitable substituent. Unless otherwise indicated, an“optionally substituted” group may have a substituent at eachsubstitutable position of the group, and when more than one position inany given structure may be substituted with more than one substituentselected from a specified group, the substituent may be either the sameor different at every position. Combinations of substituents envisionedby this invention are preferably those that result in the formation ofstable or chemically feasible compounds.

A stable compound or chemically feasible compound is one in which thechemical structure is not substantially altered when kept at atemperature from about −80° C. to about +40° C., in the absence ofmoisture or other chemically reactive conditions, for at least a week,or a compound which maintains its integrity long enough to be useful fortherapeutic or prophylactic administration to a patient.

The phrase “one or more substituents”, as used herein, refers to anumber of substituents that equals from one to the maximum number ofsubstituents possible based on the number of available bonding sites,provided that the above conditions of stability and chemical feasibilityare met.

As used herein, the term “independently selected” means that the same ordifferent values may be selected for multiple instances of a givenvariable in a single compound.

As used herein, the term “aromatic” includes aryl and heteroaryl groupsas described generally below and herein.

The term “aliphatic” or “aliphatic group”, as used herein, means anoptionally substituted straight-chain or branched C₁₋₁₂ hydrocarbon. Forexample, suitable aliphatic groups include optionally substitutedlinear, branched or cyclic alkyl, alkenyl, alkynyl groups and hybridsthereof. Unless otherwise specified, in various embodiments, aliphaticgroups have 1-12, 1-10, 1-8, 1-6, 1-4, 1-3, or 1-2 carbon atoms.

The term “alkyl”, used alone or as part of a larger moiety, refers to anoptionally substituted straight or branched chain hydrocarbon grouphaving 1-12, 1-10, 1-8, 1-6, 1-4, 1-3, or 1-2 carbon atoms.

The term “alkenyl”, used alone or as part of a larger moiety, refers toan optionally substituted straight or branched chain hydrocarbon grouphaving at least one double bond and having 2-12, 2-10, 2-8, 2-6, 2-4, or2-3 carbon atoms.

The term “alkynyl”, used alone or as part of a larger moiety, refers toan optionally substituted straight or branched chain hydrocarbon grouphaving at least one triple bond and having 2-12, 2-10, 2-8, 2-6, 2-4, or2-3 carbon atoms.

The terms “cycloaliphatic”, “carbocycle”, “carbocyclyl”, “carbocyclo”,or “carbocyclic”, used alone or as part of a larger moiety, refer to anoptionally substituted saturated or partially unsaturated cyclicaliphatic ring system having from 3 to about 14 ring carbon atoms. Insome embodiments, the cycloaliphatic group is an optionally substitutedmonocyclic hydrocarbon having 3-10, 3-8 or 3-6 ring carbon atoms.Cycloaliphatic groups include, without limitation, optionallysubstituted cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl,cyclohexyl, cyclohexenyl, cycloheptyl, cycloheptenyl, cyclooctyl,cyclooctenyl, or cyclooctadienyl. The terms “cycloaliphatic”,“carbocycle”, “carbocyclyl”, “carbocyclo”, or “carbocyclic” also includeoptionally substituted bridged or fused bicyclic rings having 6-12,6-10, or 6-8 ring carbon atoms, wherein any individual ring in thebicyclic system has 3-8 ring carbon atoms.

The term “cycloalkyl” refers to an, optionally substituted saturatedring system of about 3 to about 10 ring carbon atoms. Exemplarymonocyclic cycloalkyl rings include cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, and cycloheptyl.

The term “cycloalkenyl” refers to an optionally substituted non-aromaticmonocyclic or multicyclic ring system containing at least onecarbon-carbon double bond and having about 3 to about 10 carbon atoms.Exemplary monocyclic cycloalkenyl rings include cyclopentyl,cyclohexenyl, and cycloheptenyl.

The terms “haloaliphatic”, “haloalkyl”, “haloalkenyl” and “haloalkoxy”refer to an aliphatic, alkyl, alkenyl or alkoxy group, as the case maybe, which is substituted with one or more halogen atoms. As used herein,the term “halogen” or “halo” means F, Cl, Br, or I. The term“fluoroaliphatic” refers to a haloaliphatic wherein the halogen isfluoro, including perfluorinated aliphatic groups. Examples offluoroaliphatic groups include, without limitation, fluoromethyl,difluoromethyl, trifluoromethyl, 2-fluoroethyl, 2,2,2-trifluoroethyl,1,1,2-trifluoroethyl, 1,2,2-trifluoroethyl, and pentafluoroethyl.

The term “heteroatom” refers to one or more of oxygen, sulfur, nitrogen,phosphorus, or silicon (including, any oxidized form of nitrogen,sulfur, phosphorus, or silicon; the quaternized form of any basicnitrogen or; a substitutable nitrogen of a heterocyclic ring, forexample N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) orNR+ (as in N-substituted pyrrolidinyl)).

The terms “aryl” and “ar-”, used alone or as part of a larger moiety,e.g., “aralkyl”, “aralkoxy”, or “aryloxyalkyl”, refer to an optionallysubstituted C₆₋₁₄aromatic hydrocarbon moiety comprising one to threearomatic rings. Preferably, the aryl group is a C₆₋₁₀aryl group. Arylgroups include, without limitation, optionally substituted phenyl,naphthyl, or anthracenyl. The terms “aryl” and “ar-”, as used herein,also include groups in which an aryl ring is fused to one or morecycloaliphatic rings to form an optionally substituted cyclic structuresuch as a tetrahydronaphthyl, indenyl, or indanyl ring. The term “aryl”may be used interchangeably with the terms “aryl group”, “aryl ring”,and “aromatic ring”.

An “aralkyl” or “arylalkyl” group comprises an aryl group covalentlyattached to an alkyl group, either of which independently is optionallysubstituted. Preferably, the aralkyl group is C₆₋₁₀arylC₁₋₆alkyl,including, without limitation, benzyl, phenethyl, and naphthylmethyl.

The terms “heteroaryl” and “heteroar-”, used alone or as part of alarger moiety, e.g., “heteroaralkyl”, or “heteroaralkoxy”, refer togroups having 5 to 14 ring atoms, preferably 5, 6, 9, or 10 ring atoms;having 6, 10, or 14 π electrons shared in a cyclic array; and having, inaddition to carbon atoms, from one to five heteroatoms. In someembodiments, the heteroaryl group has 5-10 ring atoms, having, inaddition to carbon atoms, from one to five heteroatoms. A heteroarylgroup may be mono-, bi-, tri-, or polycyclic, preferably mono-, bi-, ortricyclic, more preferably mono- or bicyclic. The term “heteroatom”refers to nitrogen, oxygen, or sulfur, and includes any oxidized form ofnitrogen or sulfur, and any quaternized form of a basic nitrogen. Forexample, a nitrogen atom of a heteroaryl may be a basic nitrogen atomand may also be optionally oxidized to the corresponding N-oxide. When aheteroaryl is substituted by a hydroxy group, it also includes itscorresponding tautomer. The terms “heteroaryl” and “heteroar-”, as usedherein, also include groups in which a heteroaromatic ring is fused toone or more aryl, cycloaliphatic, or heterocycloaliphatic rings.Nonlimiting examples of heteroaryl groups include thienyl, furanyl,pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl,isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl,pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl,naphthyridinyl, pteridinyl, indolyl, isoindolyl, benzothienyl,benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzthiazolyl,quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl,quinoxalinyl, 4H-quinolizinyl, carbazolyl, acridinyl, phenazinyl,phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl,tetrahydroisoquinolinyl, and pyrido[2,3-b]-1,4-oxazin-3(4H)-one. Theterm “heteroaryl” may be used interchangeably with the terms “heteroarylring”, “heteroaryl group”, or “heteroaromatic”, any of which termsinclude rings that are optionally substituted. The term “heteroaralkyl”refers to an alkyl group substituted by a heteroaryl, wherein the alkyland heteroaryl portions independently are optionally substituted.

As used herein, the terms “heterocycle”, “heterocyclyl”, “heterocyclicradical”, and “heterocyclic ring” are used interchangeably and refer toa stable 4-10 membered ring, preferably a 3- to 8-membered monocyclic or7-10-membered bicyclic heterocyclic moiety that is either saturated orpartially unsaturated, and having, in addition to carbon atoms, one ormore, preferably one to four, heteroatoms, as defined above. When usedin reference to a ring atom of a heterocycle, the term “nitrogen”includes a substituted nitrogen. As an example, in a saturated orpartially unsaturated ring having 0-3 heteroatoms selected from oxygen,sulfur or nitrogen, the nitrogen may be N (as in3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl), or NR+ (as inN-substituted pyrrolidinyl).

A heterocyclic ring can be attached to its pendant group at anyheteroatom or carbon atom that results in a stable structure and any ofthe ring atoms can be optionally substituted. Examples of such saturatedor partially unsaturated heterocyclic radicals include, withoutlimitation, tetrahydrofuranyl, tetrahydrothienyl, piperidinyl,decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl,diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, and thiomorpholinyl. Aheterocyclyl group may be mono-, bi-, tri-, or polycyclic, preferablymono-, bi-, or tricyclic, more preferably mono- or bicyclic. The term“heterocyclylalkyl” refers to an alkyl group substituted by aheterocyclyl, wherein the alkyl and heterocyclyl portions independentlyare optionally substituted. Additionally, a heterocyclic ring alsoincludes groups in which the heterocyclic ring is fused to one or morearyl rings.

As used herein, the term “partially unsaturated” refers to a ring moietythat includes at least one double or triple bond between ring atoms. Theterm “partially unsaturated” is intended to encompass rings havingmultiple sites of unsaturation, but is not intended to include aromatic(e.g., aryl or heteroaryl) moieties, as herein defined.

The term “alkylene” refers to a bivalent alkyl group. An “alkylenechain” is a polymethylene group, i.e., —(CH₂)_(n′)—, wherein n′ is apositive integer, preferably from 1 to 6, from 1 to 4, from 1 to 3, from1 to 2, or from 2 to 3. An optionally substituted alkylene chain is apolymethylene group in which one or more methylene hydrogen atoms isoptionally replaced with a substituent. Suitable substituents includethose described below for a substituted aliphatic group and also includethose described in the specification herein. It will be appreciated thattwo substituents of the alkylene group may be taken together to form aring system. In certain embodiments, two substituents can be takentogether to form a 3-7-membered ring. The substituents can be on thesame or different atoms.

An alkylene chain also can be optionally interrupted by a functionalgroup. An alkylene chain is “interrupted” by a functional group when aninternal methylene unit is interrupted by the functional group. Examplesof suitable “interrupting functional groups” are described in thespecification and claims herein.

For purposes of clarity, all bivalent groups described herein,including, e.g., the alkylene chain linkers described above, areintended to be read from left to right, with a correspondingleft-to-right reading of the formula or structure in which the variableappears.

An aryl (including aralkyl, aralkoxy, aryloxyalkyl and the like) orheteroaryl (including heteroaralkyl and heteroarylalkoxy and the like)group may contain one or more substituents and thus may be “optionallysubstituted”. In addition to the substituents defined above and herein,suitable substituents on the unsaturated carbon atom of an aryl orheteroaryl group also include and are generally selected from -halo,—NO₂, —CN, —R⁺, —C(R⁺)═C(R⁺)₂, —C═C—R⁺, —OR⁺, —SR^(o), —S(O)R^(o),—SO₂R^(o), —SO₃R⁺, —SO₂N(R⁺)₂, —N(R⁺)₂, —NR⁺C(O)R⁺, —NR⁺C(S)R⁺,—NR⁺C(O)N(R⁺)₂, —NR⁺C(S)N(R⁺)₂, —N(R⁺)C(═NR⁺)—N(R⁺)₂,—N(R⁺)C(═NR⁺)—R^(o), —NR⁺CO₂R⁺, —NR⁺SO₂R^(o), —NR⁺SO₂N(R⁺)², —O—C(O)R⁺,—O—CO₂R⁺, —OC(O)N(R⁺)₂, —C(O)R⁺, —C(S)R^(o), —CO₂R⁺, —C(O)—C(O)R⁺,—C(O)N(R⁺)₂, —C(S)N(R⁺)₂, —C(O)N(R⁺)—OR⁺, —C(O)N(R⁺)C(═NR⁺)—N(R⁺)₂,—N(R⁺)C(═NR⁺)—N(R⁺)—C(O)R⁺, —C(═NR⁺)—N(R⁺)₂, —C(═NR⁺)—OR⁺,—N(R⁺)—N(R⁺)₂, —C(═NR⁺)—N(R⁺)—OR⁺, —C(R^(o))═N—OR⁺, —P(O)(R⁺)₂,—P(O)(OR⁺)₂, —O—P(O)—OR⁺, and —P(O)(NR⁺)—N(R⁺)₂, wherein R⁺,independently, is hydrogen or an optionally substituted aliphatic, aryl,heteroaryl, cycloaliphatic, or heterocyclyl group, or two independentoccurrences of R⁺ are taken together with their intervening atom(s) toform an optionally substituted 5-7-membered aryl, heteroaryl,cycloaliphatic, or heterocyclyl ring. Each R^(o) is an optionallysubstituted aliphatic, aryl, heteroaryl, cycloaliphatic, or heterocyclylgroup.

An aliphatic or heteroaliphatic group, or a non-aromatic carbycyclic orheterocyclic ring may contain one or more substituents and thus may be“optionally substituted”. Unless otherwise defined above and herein,suitable substituents on the saturated carbon of an aliphatic orheteroaliphatic group, or of a non-aromatic carbocyclic or heterocyclicring are selected from those listed above for the unsaturated carbon ofan aryl or heteroaryl group and additionally include the following: ═O,═S, ═C(R*)₂, ═N—N(R*)₂, ═N—OR*, ═N—NHC(O)R*, ═N—NHCO₂R^(o)═N—NHSO₂R^(o)or ═N—R* where R^(o) is defined above, and each R* is independentlyselected from hydrogen or an optionally substituted C₁₋₆ aliphaticgroup.

In addition to the substituents defined above and herein, optionalsubstituents on the nitrogen of a non-aromatic heterocyclic ring alsoinclude and are generally selected from —R⁺, —N(R⁺)₂, —C(O)R⁺, —C(O)OR⁺,—C(O)C(O)R⁺, —C(O)CH₂C(O)R⁺, —S(O)₂R⁺, —S(O)₂N(R⁺)₂, —C(S)N(R⁺)₂,—C(═NH)—N(R⁺)₂, or —N(R⁺)S(O)₂R⁺; wherein each R⁺ is defined above. Aring nitrogen atom of a heteroaryl or non-aromatic heterocyclic ringalso may be oxidized to form the corresponding N-hydroxy or N-oxidecompound. A nonlimiting example of such a heteroaryl having an oxidizedring nitrogen atom is N-oxidopyridyl.

As detailed above, in some embodiments, two independent occurrences ofR⁺ (or any other variable similarly defined in the specification andclaims herein), are taken together with their intervening atom(s) toform a monocyclic or bicyclic ring selected from 3-13-memberedcycloaliphatic, 3-12-membered heterocyclyl having 1-5 heteroatomsindependently selected from nitrogen, oxygen, or sulfur, 6-10-memberedaryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independentlyselected from nitrogen, oxygen, or sulfur.

Exemplary rings that are formed when two independent occurrences of R⁺(or any other variable similarly defined in the specification and claimsherein), are taken together with their intervening atom(s) include, butare not limited to the following: a) two independent occurrences of R⁺(or any other variable similarly defined in the specification or claimsherein) that are bound to the same atom and are taken together with thatatom to form a ring, for example, N(R⁺)₂, where both occurrences of R⁺are taken together with the nitrogen atom to form a piperidin-1-yl,piperazin-1-yl, or morpholin-4-yl group; and b) two independentoccurrences of R⁺ (or any other variable similarly defined in thespecification or claims herein) that are bound to different atoms andare taken together with both of those atoms to form a ring, for examplewhere a phenyl group is substituted with two occurrences of OR⁺

these two occurrences of R⁺ are taken together with the oxygen atoms towhich they are bound to form a fused 6-membered oxygen containing ring:

It will be appreciated that a variety of other rings (e.g., spiro andbridged rings) can be formed when two independent occurrences of R+ (orany other variable similarly defined in the specification and claimsherein) are taken together with their intervening atom(s) and that theexamples detailed above are not intended to be limiting.

Unless otherwise stated, structures depicted herein are also meant toinclude all isomeric (e.g., enantiomeric, diastereomeric, and geometric(or conformational)) forms of the structure; for example, the R and Sconfigurations for each asymmetric center, (Z) and (E) double bondisomers, and (Z) and (E) conformational isomers. Therefore, singlestereochemical isomers as well as enantiomeric, diastereomeric, andgeometric (or conformational) mixtures of the present Compounds arewithin the scope of the invention. Unless otherwise stated, alltautomeric forms of the compounds of the invention are within the scopeof the invention. Additionally, unless otherwise stated, structuresdepicted herein are also meant to include compounds that differ only inthe presence of one or more isotopically enriched atoms. For example,compounds having the present structures except for the replacement ofhydrogen by deuterium or tritium, or the replacement of a carbon by a13C— or 14C-enriched carbon are within the scope of this invention. Suchcompounds are useful, for example, as analytical tools or probes inbiological assays.

The terms “stereoisomer”, “enantiomer”, “diastereomer”, “epimer”, and“chiral center”, are used herein in accordance with the meaning each isgiven in ordinary usage by those of ordinary skill in the art. Thus,stereoisomers are compounds that have the same atomic connectivity, butdiffer in the spatial arrangement of the atoms. Enantiomers arestereoisomers that have a mirror image relationship, that is, thestereochemical configuration at all corresponding chiral centers isopposite. Diastereomers are stereoisomers having more than one chiralcenter, which differ from one another in that the stereochemicalconfiguration of at least one, but not all, of the corresponding chiralcenters is opposite. Epimers are diastereomers that differ instereochemical configuration at only one chiral center.

It is to be understood that, when a disclosed compound has at least onechiral center, the present invention encompasses one enantiomer of thecompound, substantially free from the corresponding optical isomer, aracemic mixture of both optical isomers of the compound, and mixturesenriched in one enantiomer relative to its corresponding optical isomer.When a mixture is enriched in one enantiomer relative to its opticalisomer, the mixture contains, for example, an enantiomeric excess of atleast 50%, 75%, 90%, 95%, 99%, or 99.5%.

The enantiomers of the present invention may be resolved by methodsknown to those skilled in the art, for example by formation ofdiastereoisomeric salts which may be separated, for example, bycrystallization; formation of diastereoisomeric derivatives or complexeswhich may be separated, for example, by crystallization, gas-liquid orliquid chromatography; selective reaction of one enantiomer with anenantiomer-specific reagent, for example enzymatic esterification; orgas-liquid or liquid chromatography in a chiral environment, for exampleon a chiral support for example silica with a bound chiral ligand or inthe presence of a chiral solvent. Where the desired enantiomer isconverted into another chemical entity by one of the separationprocedures described above, a further step is required to liberate thedesired enantiomeric form. Alternatively, specific enantiomers may besynthesized by asymmetric synthesis using optically active reagents,substrates, catalysts or solvents, or by converting one enantiomer intothe other by asymmetric transformation.

When a disclosed compound has at least two chiral centers, the presentinvention encompasses a diastereomer substantially free of otherdiastereomers, an enantiomeric pair of diastereomers substantially freeof other stereoisomers, mixtures of diastereomers, mixtures ofenantiomeric pairs of diastereomers, mixtures of diastereomers in whichone diastereomer is enriched relative to the other diastereomer(s), andmixtures of enantiomeric pairs of diastereomers in which oneenantiomeric pair of diastereomers is enriched relative to the otherstereoisomers. When a mixture is enriched in one diastereomer orenantiomeric pair of diastereomers pairs relative to the otherstereoisomers, the mixture is enriched with the depicted or referenceddiastereomer or enantiomeric pair of diastereomers relative to otherstereoisomers for the compound, for example, by a molar excess of atleast 50%, 75%, 90%, 95%, 99%, or 99.5%.

As used herein, the term “diastereomeric ratio” refers to the ratiobetween diastereomers which differ in the stereochemical configurationat one chiral center, relative to a second chiral center in the samemolecule. By way of example, a chemical structure with two chiralcenters provides four possible stereoisomers: R*R, R*S, S*R, and P*S,wherein the asterisk denotes the corresponding chiral center in eachstereoisomer. The diastereomeric ratio for such a mixture ofstereoisomers is the ratio of one diastereomer and its enantiomer to theother diastereomer and its enantiomer ═(R*R+S*S): (R*S+S*R).

One of ordinary skill in the art will recognize that additionalstereoisomers are possible when the molecule has more than two chiralcenters. For purposes of the present invention, the term “diastereomericratio” has identical meaning in reference to compounds with multiplechiral centers as it does in reference to compounds having two chiralcenters. Thus, the term “diastereomeric ratio” refers to the ratio ofall compounds having R*R or S*S configuration at the specified chiralcenters to all compounds having R*S or S*R configuration at thespecified chiral centers. For convenience, this ratio is referred toherein as the diastereomeric ratio at the asterisked carbon, relative tothe second specified chiral center.

The diastereomeric ratio can be measured by any analytical methodsuitable for distinguishing between diastereomeric compounds havingdifferent relative stereochemical configurations at the specified chiralcenters. Such methods include, without limitation, nuclear magneticresonance (NMR), gas chromatography (GC), and high performance liquidchromatography (HPLC) methods.

The diastereoisomeric pairs may be separated by methods known to thoseskilled in the art, for example chromatography or crystallization andthe individual enantiomers within each pair may be separated asdescribed above. Specific procedures for chromatographically separatingdiastereomeric pairs of precursors used in the preparation of compoundsdisclosed herein are provided the examples herein.

3. Description of Exemplary Compounds

In some embodiments, the compound of formula (I) is represented by:

wherein R^(1a), R^(1b), R^(1c), R^(1d), and G have the values describedherein. In certain embodiments, the compound of formula (I) isrepresented by formulas (I-a), (I-b), (I-c), or (I-l), wherein R^(1a),R^(1b), R^(1c), R^(1d), and G have the values described herein.

In some embodiments, the compound of formula (I) is represented byformula (II-i):

wherein X₁, X₂, n, and G have the values described herein.

In some embodiments, the compound of formula (II-i) is represented by:

wherein G has the values described herein. In certain embodiments, thecompound of formula (II-i) is represented by formulas (II-i-a),(II-i-b), or (II-i-c), wherein G has the values described herein.

In some embodiments, the compound of formula (I) is represented byformula (II-ii):

wherein X₁, X₂, n, and G have the values described herein.

In some embodiments, the compound of formula (II-ii) is represented by:

wherein G has the values described herein. In certain embodiments, thecompound of formula (II-ii) is represented by formula (II-ii-b) whereinG has the values described herein.

In some embodiments, the compound of formula (I) is represented byformula (III-a), (III-b), or (III-c):

wherein X₁, X₂, R^(1a), R^(1b), R^(1c), R^(1d), n, and R³ have thevalues described herein.

In some embodiments, the compound of formula (I) is represented byformula (IV-a), (IV-b), or (IV-c):

wherein X₁, X₂, n, and R³ have the values described herein. In certainembodiments, the compound of formula (IV) is represented by formula(IV-a) wherein X₁, X₂, n, and R³ have the values described herein. Incertain embodiments, the compound of formula (IV) is represented byformula (IV-b) wherein X₁, X₂, n, and R³ have the values describedherein. In certain embodiments, the compound of formula (IV) isrepresented by formula (IV-c) wherein X₁, X₂, n, and R³ have the valuesdescribed herein.

The values described below for each variable are with respect to any offormulas (I), (II), (III), (IV), or their sub-formulas as describedabove.

The variable X₁ is CH or N. The variable X₂ is CH or N. In someembodiments, at least one of X₁ and X₂ is CH. In certain embodiments, X₁is CH and X₂ is CH. In certain embodiments, X₁ is CH and X₂ is N. Incertain embodiments, X₁ is N and X₂ is CH. In certain embodiments, X₁ isN and X₂ is N.

The variable R^(1a) is hydrogen, fluoro, C₁₋₄ alkyl, or C₁₋₃fluoroalkyl. In some embodiments, R^(1a) is hydrogen, fluoro, or methyl.In certain embodiments, R^(1a) is hydrogen or methyl. In certainembodiments, R^(1a) is hydrogen.

The variable R^(1b) is hydrogen, fluoro, C₁₋₄ alkyl, orC₁₋₃-fluoroalkyl. In some embodiments, R^(1b) is hydrogen, fluoro,trifluoromethyl, methyl, ethyl, isopropyl, n-propyl, or tert-butyl. Incertain embodiments, R^(1b) is hydrogen, fluoro, or methyl. In certainembodiments, R^(1b) is hydrogen.

In some embodiments, R^(1a) and R^(1b) are taken together to form an oxogroup.

Each occurrence of the variable R^(1c) is independently hydrogen,fluoro, C₁₋₄ alkyl, or C₁₋₃ fluoroalkyl. In some embodiments, eachoccurrence of R^(1c) is independently hydrogen, fluoro, or methyl. Incertain embodiments, each occurrence of R^(1c) is independently hydrogenor methyl. In certain embodiments, R^(1c) is hydrogen.

Each occurrence of the variable R^(id) is independently hydrogen,fluoro, C₁₋₄ alkyl, or C₁₋₃ fluoroalkyl. In some embodiments, eachoccurrence of R^(1d) is independently hydrogen, fluoro, trifluoromethyl,methyl, ethyl, isopropyl, n-propyl, or tert-butyl. In certainembodiments, each occurrence of R^(1d) is independently hydrogen,fluoro, or methyl. In certain embodiments, R^(1d) is hydrogen.

The variable n is 1-2. In some embodiments, n is 1.

When R^(1a) and R^(1b) are not taken together to form an oxo group, thevariable G is —R³, —V₁—R³, —V₁-L₁-R³, -L₂-V₁—R³, -L₂-V₂—R³, or -L₁-R³,wherein L₁, L₂, V₁, V₂, and R³ have the values described herein. In somesuch embodiments, G is —V₁—R³, or —V₁-L₁-R³, wherein L₁, V₁, and R³ havethe values described herein. In certain such embodiments, G is —V₁—R³,wherein V₁, and R³ have the values described herein.

When R^(1a) and R^(1b) are taken together to form an oxo group, G is—R³, or -L₁-R³, wherein L₁, and R³ have the values described herein. Insome such embodiments, G is —R³, wherein R³ has the values describedherein.

The variable L₁ is an unsubstituted or substituted C₁₋₃ alkylene chain.In some embodiments, L₁ is —CH₂—, —CH₂CH₂—, or —CH₂CH₂CH₂—. In certainembodiments, L₁ is —CH₂—.

The variable L₂ is an unsubstituted or substituted C₂₋₃ alkylene chain.In some embodiments, L₂ is —CH₂CH₂— or —CH₂CH₂CH₂—.

The variable V₁ is —C(O)—, —C(S)—, —C(O)—CR^(A)═CR^(A)—,—C(O)—N(R^(4a))—, —C(O)—O—, or —S(O)₂—, wherein R^(A) and R^(4a) havethe values described herein. In some embodiments, V₁ is —C(O)—,—C(O)—N(R^(4a))—, or —S(O)₂—, wherein R^(4a) has the values describedherein. In certain embodiments, V₁ is —C(O)—, —C(O)—NH—, or —S(O)₂—. Inother certain embodiments, V₁ is —C(O)—.

Each occurrence of the variable R^(A) is independently hydrogen, halo,or an optionally substituted C₁₋₄aliphatic group. In some embodiments,each occurrence of R^(A) is independently hydrogen, fluoro or methyl. Incertain embodiments, R^(A) is hydrogen.

Each occurrence of the variable R^(4a) is independently hydrogen, orunsubstituted or substituted C₁₋₄ aliphatic. In certain embodiments,R^(4a) is hydrogen.

The variable V₂ is —N(R^(4a))—, —N(R^(4a))—C(O)—, —SO₂—N(R^(4a))—,—N(R^(4a))—SO₂—, —O—, —S—, —S(O)—, —N(R^(4a))—C(O)—N(R^(4a))—,—N(R^(4a))—C(O)—O—, —O—C(O)—N(R^(4a))—, or —N(R^(4a))—SO₂—N(R^(4a))—,wherein R^(4a) has the values described herein. In some embodiments, V₂is —NR^(4a))—, —NR^(4a)—C(O)—, —SO₂—N(R^(4a))—, —N(R^(4a))—SO₂—, —O—, or—S—, wherein R^(4a) has the values described herein. In certainembodiments, V₂ is —N(R^(4a))—, —O—, or —S—, wherein R^(4a) has thevalues described herein. In certain embodiments, V₂ is —NH—, or —O—.

The variable R³ is unsubstituted or substituted C₁₋₆ aliphatic,unsubstituted or substituted 3-10-membered cycloaliphatic, unsubstitutedor substituted 4-10-membered heterocyclyl having 1-4 heteroatomsindependently selected from nitrogen, oxygen, and sulfur, unsubstitutedor substituted 6-10-membered aryl, or unsubstituted or substituted5-10-membered heteroaryl having 1-5 heteroatoms independently selectedfrom nitrogen, oxygen, and sulfur.

In some embodiments, R³ is unsubstituted or substituted C₁₋₆ aliphatic,unsubstituted or substituted 3-10-membered cycloaliphatic, unsubstitutedor substituted 4-10-membered heterocyclyl having 1-4 heteroatomsindependently selected from nitrogen, oxygen, and sulfur, unsubstitutedor substituted 6-10-membered aryl, or unsubstituted or substituted5-10-membered heteroaryl having 1-5 heteroatoms independently selectedfrom nitrogen, oxygen, and sulfur; wherein:

-   -   each substitutable carbon chain atom in R³ is unsubstituted or        substituted with 1-2 occurrences of —R^(5dd);    -   each substitutable saturated ring carbon atom in R³ is        unsubstituted or substituted with ═O, ═S, ═C(R⁵)₂, ═N—N(R⁴)₂,        ═N—OR⁵, ═N—NHC(O)R⁵, ═N—NHCO₂R⁶, ═N—NHSO₂R⁶, ═N—R⁵ or —R^(5a);    -   each substitutable unsaturated ring carbon atom in R³ is        unsubstituted or is substituted with —R^(5a); and    -   each substitutable ring nitrogen atom in R³ is unsubstituted or        substituted with —R^(9b);    -   wherein R^(5dd), R⁴, R⁵, R⁶, R^(5a), and R^(9b) have the values        described herein.

In some embodiments, R³ is unsubstituted or substituted C₁₋₆ aliphatic,unsubstituted or substituted 3-10-membered cycloaliphatic, unsubstitutedor substituted 4-10-membered heterocyclyl having 1-5 heteroatomsindependently selected from nitrogen, oxygen, and sulfur, unsubstitutedor substituted 6-10-membered aryl, or unsubstituted or substituted5-10-membered heteroaryl having 1-5 heteroatoms independently selectedfrom nitrogen, oxygen, and sulfur; wherein

-   -   each substitutable carbon chain atom in R³ is unsubstituted or        substituted with 1-2 occurrences of —R^(5dd);    -   each substitutable saturated ring carbon atom in R³ is        unsubstituted or substituted with ═O, ═S, ═C(R⁵)₂, ═N—R⁵ or        —R^(5a);    -   each substitutable unsaturated ring carbon atom in R³ is        unsubstituted or is substituted with —R^(5a);    -   each substitutable ring nitrogen atom in R³ is unsubstituted or        substituted with —R^(9b);    -   wherein R^(5dd), R⁵, R^(5a), and R^(9b) have the values        described herein.

In certain embodiments, R³ is unsubstituted or substituted C₁₋₆aliphatic, unsubstituted or substituted 3-10-membered cycloaliphatic,unsubstituted or substituted 4-10-membered heterocyclyl having 1-4heteroatoms independently selected from nitrogen, oxygen, and sulfur,unsubstituted or substituted 6-10-membered aryl, or unsubstituted orsubstituted 5-10-membered heteroaryl having 1-5 heteroatomsindependently selected from nitrogen, oxygen, and sulfur; wherein:

-   -   each substitutable carbon chain atom in R³ is unsubstituted or        substituted with 1-2 occurrences of —R^(5dd);    -   each substitutable saturated ring carbon atom in R³ is        unsubstituted or substituted with —R^(5a);    -   each substitutable unsaturated ring carbon atom in R³ is        unsubstituted or is substituted with —R^(5a); the total number        of R^(5a) substituents is p; and    -   each substitutable ring nitrogen atom in R³ is unsubstituted or        substituted with —R^(9b);    -   wherein R^(5dd), R^(5a), R^(9b) and p have the values described        herein.

In some embodiments, each occurrence of R^(5dd) is independently fluoro,hydroxy, —O(C₁₋₃ alkyl), cyano, —N(R⁴)₂, —C(O)(C₁₋₃ alkyl), —CO₂H,—C(O)NH₂, —N—C(O)—(C₁₋₃ alkyl), —N—C(O)—O—(C₁₋₃ alkyl). or —C(O)NH(C₁₋₃alkyl). In certain embodiments, each occurrence of R^(5dd) isindependently fluoro, hydroxy, methoxy, ethoxy, or —C(O)NHCH₃.

Each R⁴ is independently hydrogen, unsubstituted or substituted C₁₋₆aliphatic, unsubstituted or substituted 3-10-membered cycloaliphatic,unsubstituted or substituted 4-10-membered heterocyclyl having 1-4heteroatoms independently selected from nitrogen, oxygen, and sulfur,unsubstituted or substituted 6-10-membered aryl, or unsubstituted orsubstituted 5-10-membered heteroaryl having 1-5 heteroatomsindependently selected from nitrogen, oxygen, and sulfur; or two R⁴ onthe same nitrogen atom, taken together with the nitrogen atom, form anunsubstituted or substituted 5- to 6-membered heteroaryl or anunsubstituted or substituted 4- to 8-membered heterocyclyl having, inaddition to the nitrogen atom, 0-2 ring heteroatoms selected fromnitrogen, oxygen, and sulfur.

Each R⁵ is independently hydrogen, unsubstituted or substituted C₁₋₆aliphatic, unsubstituted or substituted 3-10-membered cycloaliphatic,unsubstituted or substituted 4-10-membered heterocyclyl having 1-4heteroatoms independently selected from nitrogen, oxygen, and sulfur,unsubstituted or substituted 6-10-membered aryl, or unsubstituted orsubstituted 5-10-membered heteroaryl having 1-5 heteroatomsindependently selected from nitrogen, oxygen, and sulfur.

Each R⁶ is independently unsubstituted or substituted C₁₋₆ aliphatic, orunsubstituted or substituted 6-10-membered aryl.

Each R^(9b) is independently —C(O)R⁵, —C(O)N(R⁴)₂, —CO₂R⁶, —SO₂R⁶,—SO₂N(R⁴)₂, unsubstituted C₁₋₄ aliphatic, or C₁₋₄ aliphatic substitutedwith 1-2 independent occurrences of R⁷ or R⁸, wherein R⁷ and R⁸ have thevalues described herein. In some embodiments, each R^(9b) isindependently unsubstituted —C(O)—C₁₋₄ aliphatic, unsubstituted—C(O)—C₃₋₁₀ cycloaliphatic, or unsubstituted C₁₋₄ aliphatic. In certainembodiments, each R^(9b) is independently methyl, ethyl, isopropyl,isobutyl, n-propyl, n-butyl, tert-butyl, —C(O)-methyl, —C(O)-ethyl,—C(O)-cyclopropyl, or —C(O)-cyclobutyl.

Each R⁷ is independently unsubstituted or substituted 4-10-memberedheterocyclyl having 1-4 heteroatoms independently selected fromnitrogen, oxygen, and sulfur, unsubstituted or substituted 6-10-memberedaryl, or unsubstituted or substituted 5-10-membered heteroaryl having1-5 heteroatoms independently selected from nitrogen, oxygen, andsulfur.

Each R⁸ is independently halogen, —OH, —O(C₁₋₃ alkyl), —CN, —N(R⁴)₂,—C(O)(C₁₋₃ alkyl), —CO₂H, —CO₂(C₁₋₃ alkyl), —C(O)NH₂, or —C(O)NH(C₁₋₃alkyl), wherein R⁴ has the values described herein.

Each R^(5a) is independently halogen, —NO₂, —CN, —C(R⁵)═C(R)₂, —C≡C—R⁵,—OR⁵, —SR⁶, —S(O)R⁶, —SO₂R⁶, —SO₂N(R⁴)₂, —N(R⁴)₂, —NR⁴C(O)R⁵,—NR⁴C(O)N(R⁴)₂, —NR⁴CO₂R⁶, —OC(O)N(R⁴)₂, —C(O)R⁵, —C(O)N(R⁴)₂,—C(═NR⁴)—N(R⁴)₂, —C(═NR⁴)—OR⁵, —N(R⁴)—N(R⁴)₂, —N(R⁴)C(═NR⁴)—N(R⁴)₂,—N(R⁴)SO₂R⁶, —N(R⁴)SO₂N(R⁴)₂, —P(O)(R⁵)₂, —P(O)(OR⁵)₂, unsubstituted orsubstituted C₁₋₆ aliphatic, unsubstituted or substituted 3-10-memberedcycloaliphatic, unsubstituted or substituted 4-10-membered heterocyclylhaving 1-4 heteroatoms independently selected from nitrogen, oxygen, andsulfur, unsubstituted or substituted 6-10-membered aryl, orunsubstituted or substituted 5-10-membered heteroaryl having 1-5heteroatoms independently selected from nitrogen, oxygen, and sulfur; ortwo adjacent R^(5a), taken together with the intervening ring atoms,form an unsubstituted or substituted fused aromatic ring or anunsubstituted or substituted non-aromatic ring having 0-3 heteroatomsindependently selected from nitrogen, oxygen, and sulfur, wherein R⁵,R⁶, and R⁴ have the values described herein.

In some embodiments, each R^(5a) is independently halogen, cyano,hydroxy, C₁₋₄ alkyl, C₁₋₃ fluoroalkyl, —O—C₁₋₃ alkyl, —O—C₁₋₃fluoroalkyl, —NHC(O)C₁₋₃ alkyl, —C(O)NHC₁₋₃ alkyl, —NHC(O)NHC₁₋₃ alkyl,—NHS(O)₂C₁₋₃ alkyl, —NHC₁₋₃ alkyl, —N(C₁₋₃ alkyl)₂, 3-10-memberedcycloaliphatic substituted with 0-2 occurrences of —R^(7a),4-10-membered heterocyclyl having 1-4 heteroatoms independently selectedfrom nitrogen, oxygen, and sulfur substituted with 0-2 occurrences of—R^(7a), 6-10-membered aryl substituted with 0-2 occurrences of —R^(7a),or 5-10-membered heteroaryl having 1-5 heteroatoms independentlyselected from nitrogen, oxygen, and sulfur substituted with 0-2occurrences of —R^(7a), wherein R^(7a) has the values described herein.

In certain embodiments, each R^(5a) is independently chloro, fluoro,hydroxy, methoxy, ethoxy, n-propoxy, isopropoxy, cyano, trifluoromethyl,methyl, ethyl, isopropyl, isobutyl, n-propyl, tert-butyl or phenyl.

Each occurrence of the variable R^(7a) is independently halogen, C₁₋₄alkyl, C₁₋₃ fluoroalkyl, —O—C₁₋₃ alkyl, —O—C₁₋₃ fluoroalkyl, cyano,hydroxy, —NHC(O)C₁₋₃ alkyl, —NHC₁₋₃ alkyl, —N(C₁₋₃ alkyl)₂, —C(O)NHC₁₋₃alkyl, —NHC(O)NHC₁₋₃ alkyl, or —NHS(O)₂C₁₋₃ alkyl.

The variable p is 1-2. In some embodiments, p is 1.

In certain embodiments, R³ is unsubstituted or substituted C₁₋₆aliphatic. In certain embodiments, each substitutable carbon chain atomin R³ is unsubstituted or substituted with 1-2 occurrences of —R^(5dd),wherein R^(5dd) has the values described herein. In certain embodiments,R³ is methyl, ethyl, n-propyl, isopropyl, tert-butyl, n-butyl,iso-butyl, pentyl, hexyl, butenyl, propenyl, pentenyl, or hexenyl,wherein each of the forementioned groups is unsubstituted orsubstituted. In certain embodiments, R³ is methyl, ethyl, n-propyl,isopropyl, tert-butyl, n-butyl, iso-butyl, pentyl, hexyl, butenyl,propenyl, pentenyl, or hexenyl, wherein each substitutable carbon chainatom in R³ is unsubstituted or substituted with 1-2 occurrences of—R^(5dd), wherein R^(5dd) has the values described herein.

In certain embodiments, R³ is unsubstituted or substituted 3-10-memberedcycloaliphatic, unsubstituted or substituted 4-10-membered heterocyclylhaving 1-4 heteroatoms independently selected from nitrogen, oxygen, andsulfur, unsubstituted or substituted 6-10-membered aryl, orunsubstituted or substituted 5-10-membered heteroaryl having 1-5heteroatoms independently selected from nitrogen, oxygen, and sulfur.

In certain embodiments, R³ is unsubstituted or substituted 3-10-memberedcycloaliphatic, unsubstituted or substituted 4-10-membered heterocyclylhaving 1-4 heteroatoms independently selected from nitrogen, oxygen, andsulfur, unsubstituted or substituted 6-10-membered aryl, orunsubstituted or substituted 5-10-membered heteroaryl having 1-5heteroatoms independently selected from nitrogen, oxygen, and sulfur,wherein:

each substitutable saturated ring carbon atom in R³ is unsubstituted orsubstituted with ═O, ═S, ═C(R⁵)₂, ═N—N(R⁴)₂, ═N—OR⁵, ═N—NHC(O)R⁵,═N—NHCO₂R⁶, ═N—NHSO₂R⁶, ═N—R⁵ or —R^(5a);

each substitutable unsaturated ring carbon atom in R³ is unsubstitutedor is substituted with —R^(5a); and

each substitutable ring nitrogen atom in R³ is unsubstituted orsubstituted with —R^(9b);

wherein R⁴, R⁵, R⁶, R^(5a), and R^(9b) have the values described herein.

In certain embodiments, R³ is unsubstituted or substituted 3-10-memberedcycloaliphatic, unsubstituted or substituted 4-10-membered heterocyclylhaving 1-5 heteroatoms independently selected from nitrogen, oxygen, andsulfur, unsubstituted or substituted 6-10-membered aryl, orunsubstituted or substituted 5-10-membered heteroaryl having 1-5heteroatoms independently selected from nitrogen, oxygen, and sulfur,wherein:

each substitutable saturated ring carbon atom in R³ is unsubstituted orsubstituted with ═O, ═S, C(R⁵)₂, ═N—R⁵ or —R^(5a);

each substitutable unsaturated ring carbon atom in R³ is unsubstitutedor is substituted with —R^(5a);

each substitutable ring nitrogen atom in R³ is unsubstituted orsubstituted with —R^(9b);

wherein R⁵, R^(5a), and R^(9b) have the values described herein.

In certain embodiments, R³ is unsubstituted or substituted 3-10-memberedcycloaliphatic, unsubstituted or substituted 4-10-membered heterocyclylhaving 1-4 heteroatoms independently selected from nitrogen, oxygen, andsulfur, unsubstituted or substituted 6-10-membered aryl, orunsubstituted or substituted 5-10-membered heteroaryl having 1-5heteroatoms independently selected from nitrogen, oxygen, and sulfur,wherein:

each substitutable saturated ring carbon atom in R³ is unsubstituted orsubstituted with —R^(5a);

each substitutable unsaturated ring carbon atom in R³ is unsubstitutedor is substituted with —R^(5a);

the total number of R^(5a) substituents is p; and

each substitutable ring nitrogen atom in R³ is unsubstituted orsubstituted with —R^(9b);

wherein R^(5a), R^(9b) and p have the values described herein.

In certain embodiments, R³ is furanyl, thienyl, pyrrolyl, oxazolyl,thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl,triazolyl, thiadiazolyl, phenyl, naphthyl, pyranyl, pyridyl,pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, indolizinyl,imidazopyridyl, indolyl, isoindolyl, indazolyl, benzimidazolyl,benzthiazolyl, benzothienyl, benzofuranyl, benzoxazolyl, benzodioxolyl,benzthiadiazolyl, 2,3-dihydrobenzofuranyl, 4H-furo[3,2-b]pyrrolyl,pyrazolopyrimidinyl, purinyl, quinolyl, isoquinolyl,tetrahydroquinolinyl, tetrahydroisoquinolinyl, cinnolinyl, phthalazinyl,quinazolinyl, quinoxalinyl, naphthyridinyl, pteridinyl,tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothienyl, indanyl,tetrahydroindazolyl, pyrrolidinyl, pyrrolidonyl, piperidinyl,pyrrolinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl,diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, thiomorpholinyl,quinuclidinyl, phenanthridinyl, tetrahydronaphthyl, indolinyl,benzodioxanyl, chromanyl, cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl, cyclooctyl, cyclopentenyl, cyclohexenyl,cycloheptenyl, cyclooctenyl, bicycloheptanyl, bicyclooctanyl, oradamantyl; wherein:

each substitutable saturated ring carbon atom in R³ is unsubstituted orsubstituted with ═O, ═S, ═C(R⁵)₂, ═N—N(R⁴)₂, ═N—OR⁵, ═N—NHC(O)R⁵,═N—NHCO₂R⁶, ═N—NHSO₂R⁶, ═N—R⁵ or —R^(5a);

each substitutable unsaturated ring carbon atom in R³ is unsubstitutedor is substituted with —R^(5a); and

each substitutable ring nitrogen atom in R³ is unsubstituted orsubstituted with —R^(9b);

wherein R⁴, R⁵, R⁶, R^(5a), and R^(9b) have the values described herein.

In certain embodiments, R³ is furanyl, thienyl, pyrrolyl, oxazolyl,thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl,triazolyl, thiadiazolyl, phenyl, naphthyl, pyranyl, pyridyl,pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, indolizinyl,imidazopyridyl, indolyl, isoindolyl, indazolyl, benzimidazolyl,benzthiazolyl, benzothienyl, benzofuranyl, benzoxazolyl, benzodioxolyl,benzthiadiazolyl, 2,3-dihydrobenzofuranyl, 4H-furo[3,2-b]pyrrolyl,pyrazolopyrimidinyl, purinyl, quinolyl, isoquinolyl,tetrahydroquinolinyl, tetrahydroisoquinolinyl, cinnolinyl, phthalazinyl,quinazolinyl, quinoxalinyl, naphthyridinyl, pteridinyl,tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothienyl, indanyl,tetrahydroindazolyl, pyrrolidinyl, pyrrolidonyl, piperidinyl,pyrrolinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl,diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, thiomorpholinyl,quinuclidinyl, phenanthridinyl, tetrahydronaphthyl, indolinyl,benzodioxanyl, chromanyl, cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl, cyclooctyl, cyclopentenyl, cyclohexenyl,cycloheptenyl, cyclooctenyl, bicycloheptanyl, bicyclooctanyl, oradamantyl; wherein:

each substitutable saturated ring carbon atom in R³ is unsubstituted orsubstituted with ═O, ═S, ═C(R⁵)₂, ═N—R⁵ or —R^(5a);

each substitutable unsaturated ring carbon atom in R³ is unsubstitutedor is substituted with —R^(5a);

each substitutable ring nitrogen atom in R³ is unsubstituted orsubstituted with —R^(9b);

wherein R^(5a) and R^(9b) have the values described herein.

In certain embodiments, R³ is furanyl, thienyl, pyrrolyl, oxazolyl,thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl,triazolyl, thiadiazolyl, phenyl, naphthyl, pyranyl, pyridyl,pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, indolizinyl,imidazopyridyl, indolyl, isoindolyl, indazolyl, benzimidazolyl,benzthiazolyl, benzothienyl, benzofuranyl, benzoxazolyl, benzodioxolyl,benzthiadiazolyl, 2,3-dihydrobenzofuranyl, 4H-furo[3,2-b]pyrrolyl,pyrazolopyrimidinyl, purinyl, quinolyl, isoquinolyl,tetrahydroquinolinyl, tetrahydroisoquinolinyl, cinnolinyl, phthalazinyl,quinazolinyl, quinoxalinyl, naphthyridinyl, pteridinyl,tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothienyl, indanyl,tetrahydroindazolyl, pyrrolidinyl, pyrrolidonyl, piperidinyl,pyrrolinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl,diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, thiomorpholinyl,quinuclidinyl, phenanthridinyl, tetrahydronaphthyl, indolinyl,benzodioxanyl, chromanyl, cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl, cyclooctyl, cyclopentenyl, cyclohexenyl,cycloheptenyl, cyclooctenyl, bicycloheptanyl, bicyclooctanyl, oradamantyl; wherein:

each substitutable saturated ring carbon atom in R³ is unsubstituted orsubstituted with —R^(5a);

each substitutable unsaturated ring carbon atom in R³ is unsubstitutedor is substituted with —R^(5a);

the total number of R^(5a) substituents is p; and

each substitutable ring nitrogen atom in R³ is unsubstituted orsubstituted with —R^(9b);

wherein R^(5a), R^(9b) and p have the values described herein.

In certain embodiments, R³ is furanyl, thienyl, pyrrolyl, oxazolyl,thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl,triazolyl, thiadiazolyl, phenyl, pyranyl, pyridyl, pyridazinyl,pyrimidinyl, pyrazinyl, or triazinyl, wherein:

each substitutable unsaturated ring carbon atom in R³ is unsubstitutedor is substituted with 1-2 occurrences of —R^(5a);

each R^(5a) is independently chloro, fluoro, hydroxy, methoxy, ethoxy,n-propoxy, isopropoxy, cyano, trifluoromethyl, methyl, ethyl, isopropyl,isobutyl, n-propyl, tert-butyl or phenyl;

each substitutable ring nitrogen atom in R³ is unsubstituted orsubstituted with —R^(9b); and

each R^(9b) is independently methyl, ethyl, isopropyl, isobutyl,n-propyl, n-butyl, tert-butyl, —C(O)-methyl, —C(O)-ethyl,—C(O)-cyclopropyl, or —C(O)-cyclobutyl.

In certain embodiments, R³ is indolizinyl, imidazopyridyl, indolyl,indazolyl, benzimidazolyl, benzthiazolyl, benzothienyl, benzofuranyl,benzoxazolyl, benzthiadiazolyl, pyrazolopyrimidinyl, purinyl, quinolyl,isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl,naphthyridinyl, naphthyl, or pteridinyl; wherein:

each substitutable unsaturated ring carbon atom in R³ is unsubstitutedor is substituted with 1-2 occurrences of —R^(5a);

each R^(5a) is independently chloro, fluoro, hydroxy, methoxy, ethoxy,n-propoxy, isopropoxy, cyano, trifluoromethyl, methyl, ethyl, isopropyl,isobutyl, n-propyl, tert-butyl or phenyl;

each substitutable ring nitrogen atom in R³ is unsubstituted orsubstituted with —R^(9b); and

each R^(9b) is independently methyl, ethyl, isopropyl, isobutyl,n-propyl, n-butyl, tert-butyl, —C(O)-methyl, —C(O)-ethyl,—C(O)-cyclopropyl, or —C(O)-cyclobutyl.

In certain embodiments, R³ is tetrahydrofuranyl, tetrahydropyranyl,tetrahydrothienyl, pyrrolidinyl, pyrrolidonyl, piperidinyl, pyrrolinyl,oxazolidinyl, piperazinyl, dioxanyl, diazepinyl, oxazepinyl,thiazepinyl, morpholinyl, thiomorpholinyl, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopentenyl,cyclohexenyl, cycloheptenyl, or cyclooctenyl; wherein:

each substitutable saturated ring carbon atom in R³ is unsubstituted orsubstituted with —R^(5a);

each substitutable unsaturated ring carbon atom in R³ is unsubstitutedor is substituted with —R^(5a);

the total number of R^(5a) substituents is p;

p is 1-2;

each substitutable ring nitrogen atom in R³ is unsubstituted orsubstituted with —R^(9b);

each R^(5a) is independently chloro, fluoro, hydroxy, methoxy, ethoxy,n-propoxy, isopropoxy, cyano, trifluoromethyl, methyl, ethyl, isopropyl,isobutyl, n-propyl, tert-butyl or phenyl; and

each R^(9b) is independently methyl, ethyl, isopropyl, isobutyl,n-propyl, n-butyl, tert-butyl, —C(O)-methyl, —C(O)-ethyl,—C(O)-cyclopropyl, or —C(O)-cyclobutyl.

In certain embodiments, R³ is tetrahydroindazolyl, bicycloheptanyl,bicyclooctanyl, adamantyl, isoindolyl, benzodioxolyl,2,3-dihydrobenzofuranyl, 4H-furo[3,2-b]pyrrolyl, quinuclidinyl,tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl,tetrahydronaphthyl, indolinyl, benzodioxanyl, chromanyl,tetrahydroindazolyl, or indanyl; wherein:

-   -   each substitutable saturated ring carbon atom in R³ is        unsubstituted or substituted with —R^(5a);    -   each substitutable unsaturated ring carbon atom in R³ is        unsubstituted or is substituted with —R^(5a);    -   the total number of R^(5a) substituents is p;    -   p is 1-2;    -   each substitutable ring nitrogen atom in R³ is unsubstituted or        substituted with —R^(9b);    -   each R^(5a) is independently chloro, fluoro, hydroxy, methoxy,        ethoxy, n-propoxy, isopropoxy, cyano, trifluoromethyl, methyl,        ethyl, isopropyl, isobutyl, n-propyl, tert-butyl or phenyl; and    -   each R^(9b) is independently methyl, ethyl, isopropyl, isobutyl,        n-propyl, n-butyl, tert-butyl, —C(O)-methyl, —C(O)-ethyl,        —C(O)-cyclopropyl, or —C(O)-cyclobutyl.

In some embodiments, when R^(1a) and R^(1b) are not taken together toform an oxo group, G is:

wherein X and Ring C have the values described herein.

In certain such embodiments, G is:

wherein Ring C has the values described herein.

The variable X is —C(O)— or -L_(2a)-R^(3aa)—V_(2a)—, wherein L_(2a),R^(3aa), and V_(2a) have the values described herein. In someembodiments, X is —C(O)—. In some embodiments, X is-L_(2a)-R^(3aa)—V_(2a)—, wherein L_(2a), R^(3aa), and V_(2a) have thevalues described herein. In some embodiments, X is —C(O)—,

wherein V_(2a) and t have the values described herein.

In certain embodiments, X is —C(O)—,

In certain embodiments, X is —C(O)—, X-ii, X-xi, X-xii, X-xxii, X-xxiv,or X-xxv.

Ring C is a 4-7 membered heterocyclic ring containing one nitrogen atom,wherein the nitrogen atom is not the atom bound to X, and wherein thenitrogen atom in Ring C is substituted with R^(9bb) and Ring C isunsubstituted or substituted by 1-4 occurrences of R^(5b); whereinR^(9bb), X, and R^(5b) have the values described herein. In someembodiments, Ring C is a 4-7 membered heterocyclic ring containing onenitrogen atom, wherein the nitrogen atom is not the atom bound to X, andwherein the nitrogen atom in Ring C is substituted with R^(9bb) and RingC is unsubstituted or substituted by 1-2 occurrences of R^(5b); whereinR^(9bb), X, and R^(5b) have the values described herein.

In certain embodiments, Ring C is:

wherein Ring C is unsubstituted or substituted with 1 occurrence ofR^(5b), wherein R^(9bb) and R^(5b) have the values described herein. Incertain embodiments, Ring C is:

wherein R^(9bb), z and R^(5bb) have the values described herein.

The variable V_(2a) is a bond, —NH—C(O)—, —NH—S(O)₂—, or —NH—C(O)—NH—.In some embodiments, V_(2a) is a bond or —NH—C(O)—. In certainembodiments, V_(2a) is a bond. In certain embodiments, V_(2a) is—NH—C(O)—.

The variable t is 0-2. In some embodiments, t is 0-1. In certainembodiments, t is 0. In certain embodiments, t is 1. In certainembodiments, t is 2.

The variable L_(2a) is a bond or unsubstituted or substituted C₁₋₃alkylene chain. In some embodiments, L_(2a) is a bond, —CH₂—, —CH₂CH₂—,or —CH₂CH₂CH₂—. In certain embodiments, L_(2a) is a bond. In certainembodiments, L_(2a) is —CH₂—. In certain embodiments, L_(2a) is—CH₂CH₂—.

The variable R^(3aa) is a 6-membered aromatic ring containing 0-2nitrogen atoms which is unsubstituted or substituted with 1-2independent occurrences of R^(4c), wherein R^(4c) has the valuesdescribed herein. In some embodiments, R^(3aa) is phenyl or pyridyl,each of which is unsubstituted or substituted with 1-2 independentoccurrences of R^(4c), wherein R^(4c) has the values described herein.In some embodiments, R^(3aa) is:

wherein each ring is unsubstituted or substituted with 1-2 independentoccurrences of R^(4c).

The variable R^(4c) is chloro, fluoro, cyano, hydroxy, methoxy, ethoxy,trifluoromethoxy, trifluoromethyl, methyl, or ethyl. In someembodiments, R^(4c) is chloro, fluoro, methyl or ethyl.

The variable z is 0-1. In some embodiments, z is 0. In some embodiments,z is 1.

Each occurrence of the variable R^(5b) is independently chloro, fluoro,hydroxy, methyl, ethyl, methoxy, ethoxy, trifluoromethyl,trifluoromethoxy, —C(O)NH₂, or —CO₂H. In some embodiments, eachoccurrence of the variable R^(5b) is independently chloro, fluoro,hydroxy, methyl, or ethyl. In certain embodiments, each occurrence ofthe variable R^(5b) is methyl.

The variable R^(5bb) is hydrogen or methyl. In some embodiments, R^(5bb)is hydrogen. In some embodiments, R^(5bb) is methyl.

The variable R^(9bb) is hydrogen, unsubstituted C(O)—O—C₁₋₆ aliphatic,unsubstituted C(O)—C₁₋₅ aliphatic, unsubstituted C(O)—C₃₋₁₀cycloaliphatic, or unsubstituted C₁₋₆ aliphatic. In some embodiments,R^(9bb) is hydrogen, methyl, ethyl, isopropyl, or tert-butoxycarbonyl.In some embodiments, R^(9bb) is methyl, ethyl, or isopropyl. In certainembodiments, R^(9bb) is hydrogen.

In certain embodiments, the compound of formula (I) is represented by:

wherein:

R^(1a) is hydrogen, fluoro, or methyl;

R^(1b) is hydrogen, fluoro, trifluoromethyl, methyl, ethyl, isopropyl,n-propyl, or tert-butyl; or R^(1a) and R^(1b) are taken together to forman oxo group;

each occurrence of R^(1c) is independently hydrogen, fluoro, or methyl;and

each occurrence of R^(1d) is independently hydrogen, fluoro,trifluoromethyl, methyl, ethyl, isopropyl, n-propyl, or tert-butyl;

wherein G has the values described herein.

In such embodiments, when R^(1a) and R^(1b) are not taken together toform an oxo group;

G is —V₁—R³, or —V₁-L₁-R³;

V₁ is —C(O)—;

L₁ is —CH₂—;

R^(1a) is hydrogen;

R^(1b) is hydrogen, fluoro, or methyl;

R^(1c) is hydrogen; and

each occurrence of R^(1d) is independently hydrogen, fluoro, or methyl;

wherein R³ has the values described herein.

In such embodiments, where R^(1a) and R^(1b) are taken together to forman oxo group;

G is —R³, or -L₁-R³;

R^(1c) is hydrogen; and

each occurrence of R^(1d) is independently hydrogen, fluoro, or methyl;

wherein L₁ and R³ have the values described herein.

In certain embodiments, the compound of formula (I) is represented by:

wherein:

R^(1a) is hydrogen, fluoro, or methyl;

R^(1b) is hydrogen, fluoro, trifluoromethyl, methyl, ethyl, isopropyl,n-propyl, or tert-butyl; or R^(1a) and R^(1b) are taken together to forman oxo group;

each occurrence of R^(1c) is independently hydrogen, fluoro, or methyl;and

each occurrence of R^(1d) is independently hydrogen, fluoro,trifluoromethyl, methyl, ethyl, isopropyl, n-propyl, or tert-butyl;

wherein G has the values described herein.

In such embodiments, when R^(1a) and R^(1b) are not taken together toform an oxo group;

G is —V₁—R³, or —V₁-L₁-R³;

V₁ is —C(O)—;

L₁ is —CH₂—;

R^(1a) is hydrogen;

R^(1b) is hydrogen, fluoro, or methyl;

R^(1c) is hydrogen; and

each occurrence of R^(1d) is independently hydrogen, fluoro, or methyl;

wherein R³ has the values described herein.

In such embodiments, where R^(1a) and R^(1b) are taken together to forman oxo group;

G is —R³, or -L₁-R³;

R^(1c) is hydrogen; and

each occurrence of R^(1d) is independently hydrogen, fluoro, or methyl;

wherein L₁ and R³ have the values described herein.

In certain embodiments, the compound of formula (I) is represented by:

wherein:

R^(1a) is hydrogen, fluoro, or methyl;

R^(1b) is hydrogen, fluoro, trifluoromethyl, methyl, ethyl, isopropyl,n-propyl, or tert-butyl; or R^(1a) and R^(1b) are taken together to forman oxo group;

each occurrence of R^(1c) is independently hydrogen, fluoro, or methyl;and

each occurrence of R^(1d) is independently hydrogen, fluoro,trifluoromethyl, methyl, ethyl, isopropyl, n-propyl, or tert-butyl;

wherein G has the values described herein.

In such embodiments, when R^(1a) and R^(1b) are not taken together toform an oxo group;

G is —V₁—R³, or —V₁-L₁-R³;

V₁ is —C(O)—;

L₁ is —CH₂—;

R^(1a) is hydrogen;

R^(1b) is hydrogen, fluoro, or methyl;

R^(1c) is hydrogen; and

each occurrence of R^(1d) is independently hydrogen, fluoro, or methyl;

wherein R³ has the values described herein.

In such embodiments, where R^(1a) and R^(1b) are taken together to forman oxo group;

G is —R³, or -L₁-R³;

R^(1c) is hydrogen; and

each occurrence of R^(1d) is independently hydrogen, fluoro, or methyl;

wherein L₁ and R³ have the values described herein.

In certain embodiments, the compound of formula (I) is represented by:

wherein:

X₁ is CH or N;

X₂ is CH or N;

n is 1-2;

R^(1d) is hydrogen;

R^(1b) is hydrogen, fluoro, or methyl;

R^(1c) is hydrogen;

each occurrence of R^(1d) is independently hydrogen, fluoro, or methyl;and

wherein Ring C and X have the values described herein.

In such embodiments:

n is 1;

R^(1b) is hydrogen; and

R^(1d) is hydrogen.

In certain embodiments, the compound of formula (I) is represented by:

wherein:

X₁ is CH or N;

X₂ is CH or N;

n is 1-2;

R^(9bb) is hydrogen, methyl, ethyl, isopropyl, or tert-butoxycarbonyl;

X is —C(O)—, X-a, X-b, X-c, X-d, X-e, X-f, or X-g;

Ring C is unsubstituted or substituted with one occurrence of R^(5b);and

z, R^(5b), t, and V_(2a) have the values described herein.

In certain such embodiments,

n is 1; and

R^(5b) is methyl.

In certain embodiments, the compound of formula (I) is represented by:

wherein:

R^(1a) is hydrogen;

R^(1b) is hydrogen, fluoro, or methyl;

R^(1c) is hydrogen;

each occurrence of R^(1d) is independently hydrogen, fluoro, or methyl;

R^(9bb) is hydrogen, methyl, ethyl, isopropyl, or tert-butoxycarbonyl;

X is —C(O)—, X-ii, X-xi, X-xii, X-xxiv, or X-xxv;

R^(9bb) is hydrogen or methyl; and

z has the values described herein.

In certain such embodiments,

R^(1b) is hydrogen;

R^(1d) K is hydrogen;

R^(5bb) is methyl; and

z is 1.

In certain embodiments, the compound of formula (I) is represented by:

wherein:

R^(1a) is hydrogen;

R^(1b) is hydrogen, fluoro, or methyl;

R^(1c) is hydrogen;

each occurrence of R^(1d) is independently hydrogen, fluoro, or methyl;

R^(9bb) is hydrogen, methyl, ethyl, isopropyl, or tert-butoxycarbonyl;

X is —C(O)—, X-ii, X-xi, X-xii, X-xxii, X-xxiv, or X-xxv;

R^(9bb) is hydrogen or methyl; and

z has the values described herein.

In certain such embodiments,

R^(5bb) is hydrogen;

R^(1d) is hydrogen;

R^(5bb) is methyl; and

z is 1.

In certain embodiments, the compound of formula (I) is represented by:

wherein:

R^(1a) is hydrogen;

R^(1b) is hydrogen, fluoro, or methyl;

R^(1c) is hydrogen;

each occurrence of R^(1d) is independently hydrogen, fluoro, or methyl;

R^(9bb) is hydrogen, methyl, ethyl, isopropyl, or tert-butoxycarbonyl;

X is —C(O)—, X-ii, X-xi, X-xii, X-xxii, X-xxiv, or X-xxv;

R^(5bb) is hydrogen or methyl; and

z has the values described herein.

In certain such embodiments,

R^(1b) is hydrogen;

R^(1d) is hydrogen;

R^(5bb) is methyl; and

z is 1.

In certain embodiments, the compound of formula (I) is represented by:

wherein:

G is —V₁—R³, or —V₁-L₁-R³;

V₁ is —C(O)—;

L₁ is —CH₂—;

R^(1a) is hydrogen;

R^(1b) is hydrogen, fluoro, or methyl;

R^(1c) is hydrogen; and

each occurrence of R^(1d) is independently hydrogen, fluoro, or methyl;

wherein R³ has the values described herein.

In certain such embodiments, the compound of formula (I) is representedby formula (I-a). In certain such embodiments, the compound of formula(I) is represented by formula (I-b). In certain such embodiments, thecompound of formula (I) is represented by formula (I-c). In certain suchembodiments, the compound of formula (I) is represented by formula(I-d). In certain such embodiments, the compound of formula (I) isrepresented by formula (I-e). In certain such embodiments, the compoundof formula (I) is represented by formula (I-f). In certain suchembodiments, the compound of formula (I) is represented by formula(I-g). In certain such embodiments, the compound of formula (I) isrepresented by formula (I-h).

In certain such embodiments, the compound of formula (I) is representedby formula (I-a), wherein R^(1b) is hydrogen, and R^(1d) is hydrogen. Incertain such embodiments, the compound of formula (I) is represented byformula (I-b), wherein R^(1b) is hydrogen, and R^(1d) is hydrogen. Incertain such embodiments, the compound of formula (I) is represented byformula (I-c), wherein R^(1b) is hydrogen, and R^(1d) is hydrogen. Incertain such embodiments, the compound of formula (I) is represented byformula (I-d), wherein R^(1b) is hydrogen, and R^(1d) is hydrogen. Incertain such embodiments, the compound of formula (I) is represented byformula (I-e), wherein R^(1b) is hydrogen, and R^(1d) is hydrogen. Incertain such embodiments, the compound of formula (I) is represented byformula (I-f), wherein R^(1b) is hydrogen, and R^(1d) is hydrogen. Incertain such embodiments, the compound of formula (I) is represented byformula (I-g), wherein R^(1b) is hydrogen, and R^(1d) is hydrogen. Incertain such embodiments, the compound of formula (I) is represented byformula (I-h), wherein R^(1b) is hydrogen, and R^(1d) is hydrogen.

In certain such embodiments, the compound of formula (I) is representedby:

wherein:

G is —R³, or -L₁-R³;

R^(1c) is hydrogen; and

each occurrence of R^(1d) is independently hydrogen, fluoro, or methyl;

wherein L₁ and R³ have the values described herein.

In certain such embodiments, the compound of formula (I) is representedby formula (I-i). In certain such embodiments, the compound of formula(I) is represented by formula (I-j). In certain such embodiments, thecompound of formula (I) is represented by formula (I-k). In certain suchembodiments, the compound of formula (I) is represented by formula(I-l). In certain such embodiments, the compound of formula (I) isrepresented by formula (I-m). In certain such embodiments, the compoundof formula (I) is represented by formula (I-n). In certain suchembodiments, the compound of formula (I) is represented by formula(I-o). In certain such embodiments, the compound of formula (I) isrepresented by formula (I-p).

In certain such embodiments, the compound of formula (I) is representedby formula (I-i), wherein R^(1d) is hydrogen; and L₁ is —CH₂—, —CH₂CH₂—,or —CH₂CH₂CH₂—. In certain such embodiments, the compound of formula (I)is represented by formula (I-j), wherein R^(1d) is hydrogen; and L₁ is—CH₂—, —CH₂CH₂—, or —CH₂CH₂CH₂—. In certain such embodiments, thecompound of formula (I) is represented by formula (I-k), wherein R^(1d)is hydrogen; and L₁ is —CH₂—, —CH₂CH₂—, or —CH₂CH₂CH₂—. In certain suchembodiments, the compound of formula (I) is represented by formula(I-l), wherein R^(1d) is hydrogen; and L₁ is —CH₂—, —CH₂CH₂—, or—CH₂CH₂CH₂—. In certain such embodiments, the compound of formula (I) isrepresented by formula (I-m), wherein R^(1d) is hydrogen; and L₁ is—CH₂—, —CH₂CH₂—, or —CH₂CH₂CH₂—. In certain such embodiments, thecompound of formula (I) is represented by formula (I-n), wherein R^(1d)is hydrogen; and L₁ is —CH₂—, —CH₂CH₂—, or —CH₂CH₂CH₂—. In certain suchembodiments, the compound of formula (I) is represented by formula(I-o), wherein R^(1d) is hydrogen; and L₁ is —CH₂—, —CH₂CH₂—, or—CH₂CH₂CH₂—. In certain such embodiments, the compound of formula (I) isrepresented by formula (I-p), wherein R^(1d) is hydrogen; and L₁ is—CH₂—, —CH₂CH₂—, or —CH₂CH₂CH₂—.

Representative examples of compounds of formula (I) are shown in Table1:

I-1

I-2

I-3

I-4

I-5

I-6

I-7

I-8

I-9

I-10

I-11

I-12

I-13

I-14

I-15

I-16

I-17

I-18

I-19

I-20

I-21

I-22

I-23

I-24

I-25

I-26

I-27

I-28

I-29

I-30

I-31

I-32

I-33

I-34

I-35

I-36

I-37

I-38

I-39

I-40

I-41

I-42

I-43

I-44

I-45

I-46

I-47

I-48

I-49

I-50

I-51

I-52

I-53

I-54

I-55

I-56

I-57

I-58

I-59

I-60

I-61

I-62

I-63

I-64

I-65

I-66

I-67

I-68

I-69

I-70

I-71

I-72

I-73

I-74

I-75

I-76

I-77

I-78

I-79

I-80

I-81

I-82

I-83

I-84

I-85

I-86

I-87

I-88

I-89

I-90

I-91

I-92

I-93

I-94

I-95

I-96

I-97

I-98

I-99

I-100

I-101

I-102

I-103

I-104

I-105

I-106

I-107

I-108

I-109

I-110

I-111

I-112

I-113

I-114

I-115

I-116

I-117

I-118

I-119

I-120

I-121

I-122

I-123

I-124

I-125

I-126

I-127

I-128

I-129

I-130

I-131

I-132

I-133

I-134

I-135

I-136

I-137

I-138

I-139

I-140

I-141

I-142

I-143

I-144

I-145

I-146

I-147

I-148

I-149

I-150

I-151

I-152

I-153

I-154

I-155

I-156

I-157

I-158

I-159

I-160

I-161

I-162

I-163

I-164

I-165

I-166

I-167

I-168

I-169

I-170

I-171

I-172

I-173

I-174

I-175

I-176

I-177

I-178

I-179

I-180

I-181

I-182

I-183

I-184

I-185

I-186

I-187

I-188

I-189

I-190

I-191

I-192

I-193

I-194

I-195

I-196

I-197

I-198

I-199

I-200

I-201

I-202

I-203

I-204

I-205

I-206

I-207

I-208

I-209

I-210

I-211

I-212

I-213

I-214

I-215

I-216

I-217

I-218

I-219

I-220

I-221

I-222

I-223

I-224

I-225

I-226

I-227

I-228

I-229

I-230

I-231

I-232

I-233

I-234

I-235

I-236

I-237

I-238

I-239

I-240

I-241

The compounds in Table 1 above may also be identified by the followingchemical names:

I-12-(4-tert-butylbenzoyl)-N-hydroxy-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-7-carboxamideI-27-(biphenyl-4-ylcarbonyl)-N-hydroxy-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-2-carboxamideI-3N-hydroxy-2-(imidazo[1,2-a]pyridin-2-ylcarbonyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-7-carboxamide I-42-(2,5-dimethyl-3-furoyl)-N-hydroxy-2,3,4,5-tetrahydro-1H-pyrrolo[1,2-a][1,4]diazepine-8-carboxamide I-5N-hydroxy-2-({4-methyl-2-[4-(trifluoromethyl)phenyl]-4H-furo[3,2-b]pyrrol-5-yl}carbonyl)-2,3,4,5-tetrahydro-1H-pyrrolo[1,2-a][1,4]diazepine-8-carboxamide I-6N-hydroxy-5-[(1-methylcyclohexyl)carbonyl]-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2-carboxamide I-7N-hydroxy-2-[(5-methyl-1-phenyl-1H-pyrazol-4-yl)carbonyl]-2,3,4,5-tetrahydro-1H-pyrrolo[1,2-a][1,4]diazepine-8-carboxamide I-8N-hydroxy-5-{[1-(trifluoromethyl)cyclopropyl]carbonyl}-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2-carboxamide I-9N-hydroxy-2-[(1-methyl-1H-pyrrol-2-yl)carbonyl]-2,3,4,5-tetrahydro-1H-pyrrolo[1,2-a][1,4]diazepine-8-carboxamide I-102-(1-benzothien-3-ylcarbonyl)-N-hydroxy-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-7-carboxamide I-115-[(4,5-dichloro-1-methyl-1H-pyrrol-2-yl)carbonyl]-N-hydroxy-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2-carboxamide I-125-(4-fluorobenzyl)-N-hydroxy-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2-carboxamideI-13N-hydroxy-7-(4-methoxybenzoyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-2-carboxamideI-14N-hydroxy-7-[(1-methyl-1H-pyrrol-2-yl)carbonyl]-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-2-carboxamide I-152-[(4-acetyl-3,5-dimethyl-1H-pyrrol-2-yl)carbonyl]-N-hydroxy-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-7-carboxamide I-165-(1-adamantylcarbonyl)-N-hydroxy-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2-carboxamideI-175-[4-(benzyloxy)benzoyl]-N-hydroxy-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2-carboxamideI-182-(4-tert-butylbenzoyl)-N-hydroxy-2,3,4,5-tetrahydro-1H-pyrrolo[1,2-a][1,4]diazepine-8-carboxamide I-192-(cyclopentylcarbonyl)-N-hydroxy-2,3,4,5-tetrahydro-1H-pyrrolo[1,2-a][1,4]diazepine-8-carboxamide I-20N-hydroxy-2-[(1-methyl-1H-indol-2-yl)carbonyl]-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-7-carboxamide I-217-(1-benzofuran-2-ylcarbonyl)-N-hydroxy-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-2-carboxamide I-22N-hydroxy-2-[(5-methyl-1H-indol-2-yl)carbonyl]-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-7-carboxamide I-232-benzyl-N-hydroxy-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-7-carboxamideI-245-(cyclohexylmethyl)-N-hydroxy-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2-carboxamide I-25N-hydroxy-2-(quinolin-4-ylcarbonyl)-2,3,4,5-tetrahydro-1H-pyrrolo[1,2-a][1,4]diazepine-8-carboxamide I-26N-hydroxy-7-[(1-methylcyclohexyl)carbonyl]-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-2-carboxamide I-277-[1-adamantylcarbonyl]-N-hydroxy-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-2-carboxamideI-282-[(3,5-dimethyl-1H-indol-2-yl)carbonyl]-N-hydroxy-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-7-carboxamide I-29N-hydroxy-2-(1H-indol-2-ylcarbonyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-7-carboxamideI-30N-hydroxy-2-(2-thienylcarbonyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-7-carboxamideI-31N-hydroxy-5-[(1-methyl-1H-indol-2-yl)carbonyl]-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2-carboxamide I-32N-hydroxy-2-[(1-methyl-1H-pyrrol-2-yl)carbonyl]-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-7-carboxamide I-33N-hydroxy-2-[4-(trifluoromethyl)benzoyl]-2,3,4,5-tetrahydro-1H-pyrrolo[1,2-a][1,4]diazepine-8-carboxamide I-342-{[1-(4-chlorophenyl)cyclopropyl]carbonyl}-N-hydroxy-2,3,4,5-tetrahydro-1H-pyrrolo[1,2-a][1,4]diazepine-8-carboxamide I-352-{[2,5-dimethyl-1-(2-thienylmethyl)-1H-pyrrol-3-yl]carbonyl}-N-hydroxy-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-7-carboxamide I-365-(2,2-dimethylpropanoyl)-N-hydroxy-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2-carboxamideI-375-[2-(4-chlorophenyl)-2-methylpropanoyl]-N-hydroxy-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2-carboxamide I-382-[1-adamantylcarbonyl]-N-hydroxy-2,3,4,5-tetrahydro-1H-pyrrolo[1,2-a][1,4]diazepine-8-carboxamide I-39N-hydroxy-2-[(1-methyl-1H-pyrazol-3-yl)carbonyl]-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-7-carboxamide I-402-[(3,5-dimethyl-1H-pyrrol-2-yl)carbonyl]-N-hydroxy-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-7-carboxamide I-417-(2,2-dimethylpropanoyl)-N-hydroxy-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-2-carboxamideI-422-benzyl-N-hydroxy-1-oxo-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-7-carboxamideI-43N-hydroxy-2-(4-methylbenzoyl)-2,3,4,5-tetrahydro-1H-pyrrolo[1,2-a][1,4]diazepine-8-carboxamide I-447-(1-benzothien-2-ylcarbonyl)-N-hydroxy-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-2-carboxamide I-457-(4-tert-butylbenzoyl)-N-hydroxy-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-2-carboxamideI-46N-hydroxy-5-isopropyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2-carboxamideI-472-{[5-(aminosulfonyl)-1-methyl-1H-pyrrol-2-yl]carbonyl}-N-hydroxy-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-7-carboxamide I-48N-hydroxy-4-oxo-5-(2-phenoxyethyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2-carboxamideI-492-benzyl-N-hydroxy-1-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[1,2-a][1,4]diazepine-8-carboxamideI-50N-hydroxy-5-(4-methylpentyl)-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2-carboxamideI-512-(biphenyl-4-ylcarbonyl)-N-hydroxy-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-7-carboxamideI-522-[(1,5-dimethyl-1H-pyrazol-3-yl)carbonyl]-N-hydroxy-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-7-carboxamide I-53N-hydroxy-5-(4-methoxybenzoyl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxamide I-54N-hydroxy-2-[3-(methylsulfonyl)benzoyl]-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-7-carboxamide I-55N-hydroxy-7-[(2-methyl-1,3-thiazol-4-yl)carbonyl]-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-2-carboxamide I-562-(4-chlorobenzoyl)-N-hydroxy-2,3,4,5-tetrahydro-1H-pyrrolo[1,2-a][1,4]diazepine-8-carboxamide I-577-(4-chlorobenzoyl)-N-hydroxy-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-2-carboxamideI-58N-hydroxy-2-[(1-methyl-1H-indol-3-yl)carbonyl]-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-7-carboxamide I-592-(3,3-dimethylbutanoyl)-N-hydroxy-2,3,4,5-tetrahydro-1H-pyrrolo[1,2-a][1,4]diazepine-8-carboxamide I-607-[(3-chloro-1-benzothien-2-yl)carbonyl]-N-hydroxy-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-2-carboxamide I-612-[(3,5-dimethylisoxazol-4-yl)carbonyl]-N-hydroxy-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-7-carboxamide I-622-[1-adamantylcarbonyl]-N-hydroxy-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-7-carboxamideI-632-[(3-tert-butyl-1-methyl-1H-pyrazol-5-yl)carbonyl]-N-hydroxy-2,3,4,5-tetrahydro-1H-pyrrolo[1,2-a][1,4]diazepine-8-carboxamide I-64N-hydroxy-2-{[1-phenyl-5-(trifluoromethyl)-1H-pyrazol-4-yl]carbonyl}-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-7-carboxamide I-65N-hydroxy-4-oxo-5-(3-phenylpropyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2-carboxamideI-66N-hydroxy-2-[(2-methyl-4,5,6,7-tetrahydro-2H-indazol-3-yl)carbonyl]-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-7-carboxamide I-675-(4-tert-butylbenzyl)-N-hydroxy-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2-carboxamide I-68N-hydroxy-2-(4-methoxybenzoyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-7-carboxamideI-69N-hydroxy-2-[(5-methyl-2-thienyl)carbonyl]-2,3,4,5-tetrahydro-1H-pyrrolo[1,2- a][1,4]diazepine-8-carboxamide I-70N-hydroxy-5-[(5-pyridin-2-yl-2-thienyl)carbonyl]-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxamide I-71N-hydroxy-5-[(1-methyl-1H-pyrrol-2-yl)carbonyl]-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxamide I-725-(1-adamantylcarbonyl)-N-hydroxy-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxamide I-73N-hydroxy-2-[(2-methyl-1,3-thiazol-4-yl)carbonyl]-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-7-carboxamide I-74N-hydroxy-2-[(1-methylcyclohexyl)carbonyl]-2,3,4,5-tetrahydro-1H-pyrrolo[1,2-a][1,4]diazepine-8-carboxamide I-75N-hydroxy-2-(1H-indol-3-ylcarbonyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-7-carboxamideI-76N-hydroxy-5-[(1-methyl-1H-pyrrol-2-yl)carbonyl]-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2-carboxamide I-77N-hydroxy-5-(3-methylbutyl)-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2-carboxamideI-78N-hydroxy-2-[(2-methyl-1,3-thiazol-4-yl)carbonyl]-2,3,4,5-tetrahydro-1H-pyrrolo[1,2-a][1,4]diazepine-8-carboxamide I-792-(2,6-dichlorobenzoyl)-N-hydroxy-2,3,4,5-tetrahydro-1H-pyrrolo[1,2-a][1,4]diazepine-8-carboxamide I-80N-hydroxy-2-[(4′-methylbiphenyl-4-yl)carbonyl]-2,3,4,5-tetrahydro-1H-pyrrolo[1,2-a][1,4]diazepine-8-carboxamide I-815-benzyl-N-hydroxy-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2-carboxamideI-82N-hydroxy-2-[(5-methyl-2-phenyl-1,3-oxazol-4-yl)acetyl]-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-7-carboxamide I-835-(cyclopropylmethyl)-N-hydroxy-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2-carboxamide I-84N-hydroxy-2-(pyrazolo[1,5-a]pyrimidin-3-ylcarbonyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-7-carboxamide I-852-(2,5-dimethyl-3-furoyl)-N-hydroxy-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-7-carboxamideI-862-butyl-N-hydroxy-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-7-carboxamideI-87N-hydroxy-2-[(2-methyl-1,5-diphenyl-1H-pyrrol-3-yl)carbonyl]-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-7-carboxamide I-885-(2-ethoxyethyl)-N-hydroxy-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2-carboxamideI-89N-hydroxy-2-[(1-methyl-1H-indol-5-yl)carbonyl]-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-7-carboxamide I-90N-hydroxy-5-[(2-methyl-1,3-thiazol-4-yl)acetyl]-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2-carboxamide I-912-[(4,5-dichloro-1-methyl-1H-pyrrol-2-yl)carbonyl]-N-hydroxy-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-7-carboxamide I-9212-(cyclohexylcarbonyl)-N-hydroxy-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-7-carboxamideI-93N-hydroxy-5-[(5-methyl-1H-indol-3-yl)acetyl]-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2-carboxamide I-942-[(2,5-dimethyl-1H-pyrrol-3-yl)carbonyl]-N-hydroxy-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-7-carboxamide I-952-[(3-ethyl-1-methyl-1H-pyrazol-5-yl)carbonyl]-N-hydroxy-2,3,4,5-tetrahydro-1H-pyrrolo[1,2-a][1,4]diazepine-8-carboxamide I-962-(1-benzothien-3-ylcarbonyl)-N-hydroxy-2,3,4,5-tetrahydro-1H-pyrrolo[1,2-a][1,4]diazepine-8-carboxamide I-97N-hydroxy-5-[(3-methyl-1-benzothien-2-yl)carbonyl]-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2-carboxamide I-985-(1-benzothien-2-ylcarbonyl)-N-hydroxy-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxamide I-99N-hydroxy-2-[(5-methyl-1-phenyl-1H-pyrazol-4-yl)carbonyl]-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-7-carboxamide I-100N-hydroxy-5-(4-methoxybenzoyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2-carboxamideI-101N-hydroxy-7-[(4-methyl-2-pyridin-2-yl-1,3-thiazol-5-yl)carbonyl]-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-2-carboxamide I-102N-hydroxy-5-(1H-indol-3-ylacetyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2-carboxamideI-103N-hydroxy-4-oxo-5-[3-(trifluoromethyl)benzyl]-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2-carboxamide I-1042-[(4,5-dichloro-1-methyl-1H-pyrrol-2-yl)carbonyl]-N-hydroxy-2,3,4,5-tetrahydro-1H-pyrrolo[1,2-a][1,4]diazepine-8-carboxamide I-105N-hydroxy-5-[(1-methyl-1H-indol-2-yl)carbonyl]-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxamide I-106N-hydroxy-5-(3-phenylpropanoyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2-carboxamideI-107N-hydroxy-5-(quinolin-8-ylcarbonyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2-carboxamideI-108N-hydroxy-5-[(3-methyl-1-benzofuran-2-yl)carbonyl]-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxamide I-109N-hydroxy-4-oxo-5-[3-(1H-pyrrol-1-yl)propyl]-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2-carboxamide I-1105-(3-chlorobenzyl)-N-hydroxy-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2-carboxamideI-1112-(cyclohexylcarbonyl)-N-hydroxy-2,3,4,5-tetrahydro-1H-pyrrolo[1,2-a][1,4]diazepine-8-carboxamide I-112N7-(2-tert-butylphenyl)-N2-hydroxy-5,6-dihydroimidazo[1,2-a]pyrazine-2,7(8H)-dicarboxamideI-113N7-[1-adamantyl]-N2-hydroxy-5,6-dihydroimidazo[1,2-a]pyrazine-2,7(8H)-dicarboxamideI-114N7-biphenyl-2-yl-N2-hydroxy-5,6-dihydroimidazo[1,2-a]pyrazine-2,7(8H)-dicarboxamideI-115N7-(2,6-diethylphenyl)-N2-hydroxy-5,6-dihydroimidazo[1,2-a]pyrazine-2,7(8H)-dicarboxamideI-116N2-hydroxy-N7-phenyl-5,6-dihydroimidazo[1,2-a]pyrazine-2,7(8H)-dicarboxamideI-117N2-hydroxy-N7-(2-methylphenyl)-5,6-dihydroimidazo[1,2-a]pyrazine-2,7(8H)-dicarboxamideI-118N7-(sec-butyl)-N2-hydroxy-5,6-dihydroimidazo[1,2-a]pyrazine-2,7(8H)-dicarboxamideI-119N7-(tert-butyl)-N2-hydroxy-5,6-dihydroimidazo[1,2-a]pyrazine-2,7(8H)-dicarboxamideI-120N2-hydroxy-N7-(2-phenylethyl)-5,6-dihydroimidazo[1,2-a]pyrazine-2,7(8H)-dicarboxamideI-121N7-cyclohexyl-N2-hydroxy-5,6-dihydroimidazo[1,2-a]pyrazine-2,7(8H)-dicarboxamideI-122N2-hydroxy-N7-(5-methyl-3-phenylisoxazol-4-yl)-5,6-dihydroimidazo[1,2-a]pyrazine-2,7(8H)-dicarboxamide I-123N7-benzyl-N2-hydroxy-5,6-dihydroimidazo[1,2-a]pyrazine-2,7(8H)-dicarboxamideI-124N-hydroxy-1-oxo-2-[4-(trifluoromethyl)benzyl]-2,3,4,5-tetrahydro-1H-pyrrolo[1,2-a][1,4]diazepine-8-carboxamide I-1252-(1-benzothien-2-ylcarbonyl)-N-hydroxy-4,4-dimethyl-2,3,4,5-tetrahydro-1H-pyrrolo[1,2-a][1,4]diazepine-8-carboxamide I-126N-hydroxy-1-oxo-2-[3-(trifluoromethoxy)benzyl]-2,3,4,5-tetrahydro-1H-pyrrolo[1,2-a][1,4]diazepine-8-carboxamide I-1271-ethyl-N-hydroxy-2-[(1-methylpiperidin-4-yl)carbonyl]-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-7-carboxamide I-128N-hydroxy-3-methyl-2-[(1-methylpiperidin-4-yl)carbonyl]-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-7-carboxamide I-1291-ethyl-N-hydroxy-2-[(1-methyl-1H-pyrrol-2-yl)carbonyl]-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-7-carboxamide I-130N-hydroxy-1-isopropyl-2-{[4-(trifluoromethyl)phenyl]sulfonyl}-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-7-carboxamide I-131N-hydroxy-1-methyl-2-[(1-methylpiperidin-4-yl)carbonyl]-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-7-carboxamide I-132N2-1-adamantyl-N7-hydroxy-1-methyl-3,4-dihydropyrrolo[1,2-a]pyrazine-2,7(1H)-dicarboxamide I-1332-cyclopropyl-N-hydroxy-1-oxo-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-7-carboxamideI-134N-hydroxy-1-methyl-2-[(1-methyl-1H-indol-2-yl)carbonyl]-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-7-carboxamide I-1355-(1-adamantylcarbonyl)-N-hydroxy-4-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2-carboxamide I-136N-hydroxy-4,4-dimethyl-2-[(1-methyl-1H-indol-2-yl)carbonyl]-2,3,4,5-tetrahydro-1H-pyrrolo[1,2-a][1,4]diazepine-8-carboxamide I-1372-(2,2-dimethylpropanoyl)-N-hydroxy-4,4-dimethyl-2,3,4,5-tetrahydro-1H-pyrrolo[1,2-a][1,4]diazepine-8-carboxamide I-1382-(3-cyanobenzyl)-N-hydroxy-1-oxo-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-7-carboxamideI-1397-[(dimethylamino)acetyl]-N-hydroxy-8-methyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-2-carboxamide I-1405-(1-benzothien-2-ylcarbonyl)-N-hydroxy-4-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2-carboxamide I-141N-hydroxy-7-[(1-methyl-1H-indol-2-yl)carbonyl]-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyrazine-2-carboxamide I-142N5-cyclohexyl-N2-hydroxy-4-methyl-6,7-dihydropyrazolo[1,5-a]pyrazine-2,5(4H)-dicarboxamide I-143N-hydroxy-3-methyl-1-oxo-2-[4-(1H-pyrazol-1-yl)benzyl]-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-7-carboxamide I-1442-(4-tert-butylbenzyl)-N-hydroxy-4,4-dimethyl-1-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[1,2-a][1,4]diazepine-8-carboxamide I-145N-hydroxy-4,4-dimethyl-2-[(1-methyl-1H-pyrrol-2-yl)carbonyl]-2,3,4,5-tetrahydro-1H-pyrrolo[1,2-a][1,4]diazepine-8-carboxamide I-1462-(4-fluorobenzyl)-N-hydroxy-1-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[1,2-a][1,4]diazepine-8-carboxamide I-147N-hydroxy-4,4-dimethyl-2-[(1-methylpiperidin-4-yl)carbonyl]-2,3,4,5-tetrahydro-1H-pyrrolo[1,2-a][1,4]diazepine-8-carboxamide I-1485-(2,2-dimethylpropanoyl)-N-hydroxy-4-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2-carboxamide I-1492-(1-adamantylcarbonyl)-N-hydroxy-3-methyl-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-7-carboxamide I-1502-[(dimethylamino)acetyl]-N-hydroxy-4,4-dimethyl-2,3,4,5-tetrahydro-1H-pyrrolo[1,2-a][1,4]diazepine-8-carboxamide I-1517-[(dimethylamino)acetyl]-N-hydroxy-8-isopropyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-2-carboxamide I-1522-[(5-chloro-1-benzothien-3-yl)methyl]-N-hydroxy-1-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[1,2-a][1,4]diazepine-8-carboxamide I-153N2-(tert-butyl)-1-ethyl-N7-hydroxy-3,4-dihydropyrrolo[1,2-a]pyrazine-2,7(1H)-dicarboxamideI-154N-hydroxy-1-oxo-2-[4-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-7-carboxamide I-1552-(cyclopentylacetyl)-N-hydroxy-1-methyl-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-7-carboxamide I-1561-ethyl-N-hydroxy-2-[(1-methyl-1H-indol-2-yl)carbonyl]-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-7-carboxamide I-157N-hydroxy-7-[(1-methyl-1H-pyrrol-2-yl)carbonyl]-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyrazine-2-carboxamide I-1582-(biphenyl-4-ylcarbonyl)-N-hydroxy-3-methyl-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-7-carboxamide I-1592-(3-cyanobenzyl)-N-hydroxy-1-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[1,2-a][1,4]diazepine-8-carboxamide I-160N-hydroxy-8-methyl-7-[(1-methylpiperidin-4-yl)carbonyl]-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-2-carboxamide I-1612-(1-adamantylcarbonyl)-N-hydroxy-1-methyl-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-7-carboxamide I-1622-(1-benzothien-2-ylcarbonyl)-N-hydroxy-3-methyl-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-7-carboxamide I-163N-hydroxy-1-oxo-2-[3-(trifluoromethoxy)benzyl]-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-7-carboxamide I-1641-ethyl-N-hydroxy-2-(propylsulfonyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-7-carboxamideI-1652-(1-adamantylcarbonyl)-N-hydroxy-4,4-dimethyl-2,3,4,5-tetrahydro-1H-pyrrolo[1,2-a][1,4]diazepine-8-carboxamide I-166N-hydroxy-8-methyl-7-[(1-methyl-1H-pyrrol-2-yl)carbonyl]-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-2-carboxamide I-1677-(biphenyl-4-ylcarbonyl)-N-hydroxy-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyrazine-2-carboxamide I-1682-(cyclopentylacetyl)-N-hydroxy-4,4-dimethyl-2,3,4,5-tetrahydro-1H-pyrrolo[1,2-a][1,4]diazepine-8-carboxamide I-169N-hydroxy-8-isopropyl-7-[(1-methylpiperidin-4-yl)carbonyl]-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-2-carboxamide I-1707-(biphenyl-4-ylcarbonyl)-N-hydroxy-8-isopropyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-2-carboxamide I-171N-hydroxy-3-methyl-1-oxo-2-[3-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-7-carboxamide I-172N-hydroxy-8-isopropyl-7-[(1-methyl-1H-pyrrol-2-yl)carbonyl]-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-2-carboxamide I-1737-(1-benzothien-2-ylcarbonyl)-N-hydroxy-8-methyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-2-carboxamide I-174N-hydroxy-4-methyl-5-[(1-methylpiperidin-4-yl)carbonyl]-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2-carboxamide I-1752-(4-fluorobenzyl)-N-hydroxy-1-oxo-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-7-carboxamideI-176N-hydroxy-8-isopropyl-7-{[4-(trifluoromethyl)phenyl]sulfonyl}-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-2-carboxamide I-1777-(1-adamantylcarbonyl)-N-hydroxy-8-methyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-2-carboxamide I-178N-hydroxy-1-oxo-2-(quinolin-8-ylmethyl)-2,3,4,5-tetrahydro-1H-pynolo[1,2-a][1,4]diazepine-8-carboxamide I-1797-(cyclopentylacetyl)-N-hydroxy-8-isopropyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-2-carboxamide I-180N-hydroxy-4,4-dimethyl-2-[(5-methyl-3-phenylisoxazol-4-yl)methyl]-1-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[1,2-a][1,4]diazepine-8-carboxamide I-1817-(1-adamantylcarbonyl)-N-hydroxy-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyrazine-2-carboxamide I-1822-(1-benzothien-2-ylcarbonyl)-N-hydroxy-1-methyl-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-7-carboxamide I-183N-hydroxy-1-oxo-2-(quinolin-8-ylmethyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-7-carboxamide I-184N-hydroxy-3-methyl-2-[(1-methyl-1H-pyrrol-2-yl)carbonyl]-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-7-carboxamide I-1852-(biphenyl-4-ylcarbonyl)-N-hydroxy-4,4-dimethyl-2,3,4,5-tetrahydro-1H-pyrrolo[1,2-a][1,4]diazepine-8-carboxamide I-1862-(3-chlorobenzyl)-N-hydroxy-1-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[1,2-a][1,4]diazepine-8-carboxamide I-187N2-1-adamantyl-N8-hydroxy-4,4-dimethyl-4,5-dihydro-1H-pyrrolo[1,2-a][1,4]diazepine-2,8(3H)-dicarboxamide I-1882-[(dimethylamino)acetyl]-N-hydroxy-3-methyl-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-7-carboxamide I-1892-[3-(4-fluorophenoxy)benzyl]-N-hydroxy-1-oxo-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-7-carboxamide I-1907-(1-benzothien-2-ylcarbonyl)-N-hydroxy-8-isopropyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-2-carboxamide I-1912-(biphenyl-2-ylmethyl)-N-hydroxy-1-oxo-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-7-carboxamide I-1927-(2,2-dimethylpropanoyl)-N-hydroxy-8-isopropyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-2-carboxamide I-1932-[3-(4-fluorophenoxy)benzyl]-N-hydroxy-1-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[1,2-a][1,4]diazepine-8-carboxamide I-1947-(2,2-dimethylpropanoyl)-N-hydroxy-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyrazine-2-carboxamide I-195N-hydroxy-2-[(1-methyl-1H-pyrrol-2-yl)carbonyl]-3-phenyl-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-7-carboxamide I-1967-(cyclopentylacetyl)-N-hydroxy-8-methyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-2-carboxamide I-197N-hydroxy-2-[(5-methyl-3-phenylisoxazol-4-yl)methyl]-1-oxo-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-7-carboxamide I-1982-(cyclopropylmethyl)-N-hydroxy-3-methyl-1-oxo-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-7-carboxamide I-1997-[(dimethylamino)acetyl]-N-hydroxy-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyrazine-2-carboxamide I-2002-ethyl-N-hydroxy-1-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[1,2-a][1,4]diazepine-8-carboxamideI-2012-(2,2-dimethylpropanoyl)-1-ethyl-N-hydroxy-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-7-carboxamide I-202N-hydroxy-4-methyl-5-[(1-methyl-1H-indol-2-yl)carbonyl]-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2-carboxamide I-2032-(2,2-dimethylpropanoyl)-N-hydroxy-3-methyl-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-7-carboxamide I-204N-hydroxy-7-[(1-methylpiperidin-4-yl)carbonyl]-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyrazine-2-carboxamide I-2052-[(dimethylamino)acetyl]-1-ethyl-N-hydroxy-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-7-carboxamide I-2067-(2,2-dimethylpropanoyl)-N-hydroxy-8-methyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-2-carboxamide I-2072-cyclopropyl-N-hydroxy-1-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[1,2-a][1,4]diazepine-8-carboxamide I-208N-hydroxy-8-isopropyl-7-[(1-methyl-1H-indol-2-yl)carbonyl]-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-2-carboxamide I-2092-ethyl-N-hydroxy-1-oxo-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-7-carboxamideI-2102-[(5-chloro-1-benzothien-3-yl)methyl]-N-hydroxy-1-oxo-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-7-carboxamide I-211N-hydroxy-8-methyl-7-[(1-methyl-1H-indol-2-yl)carbonyl]-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-2-carboxamide I-212N-hydroxy-4,4-dimethyl-2-(3-methylbutyl)-1-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[1,2-a][1,4]diazepine-8-carboxamide I-213N-hydroxy-7-{[4-(trifluoromethyl)phenyl]sulfonyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyrazine-2-carboxamide I-2145-(cyclopentylacetyl)-N-hydroxy-4-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2-carboxamide I-2152-(3-chlorobenzyl)-N-hydroxy-1-oxo-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-7-carboxamideI-216N-hydroxy-1-methyl-2-[(1-methyl-1H-pyrrol-2-yl)carbonyl]-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-7-carboxamide I-217N-hydroxy-7-(propylsulfonyl)-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyrazine-2-carboxamideI-2182-(1-adamantylcarbonyl)-1-ethyl-N-hydroxy-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-7-carboxamide I-219N-hydroxy-4-methyl-5-[(1-methyl-1H-pyrrol-2-yl)carbonyl]-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2-carboxamide I-2202-(biphenyl-2-ylmethyl)-N-hydroxy-1-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[1,2-a][1,4]diazepine-8-carboxamide I-2217-(cyclopentylacetyl)-N-hydroxy-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyrazine-2-carboxamideI-2222-(cyclopentylacetyl)-N-hydroxy-3-methyl-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-7-carboxamide I-2232-(1-benzothien-2-ylcarbonyl)-1-ethyl-N-hydroxy-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-7-carboxamide I-224N-hydroxy-3-methyl-2-[(1-methyl-1H-indol-2-yl)carbonyl]-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-7-carboxamide I-2252-(cyclopentylacetyl)-1-ethyl-N-hydroxy-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-7-carboxamide I-2262-(biphenyl-4-ylcarbonyl)-1-ethyl-N-hydroxy-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-7-carboxamide I-2277-(1-adamantylcarbonyl)-N-hydroxy-8-isopropyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-2-carboxamide I-2282-[(dimethylamino)acetyl]-N-hydroxy-1-methyl-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-7-carboxamide I-2295-(biphenyl-4-ylcarbonyl)-N-hydroxy-4-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2-carboxamide I-2307-(1-benzothien-2-ylcarbonyl)-N-hydroxy-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyrazine-2-carboxamide I-2315-[(dimethylamino)acetyl]-N-hydroxy-4-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2-carboxamide I-2322-(biphenyl-4-ylcarbonyl)-N-hydroxy-1-methyl-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-7-carboxamide I-2332-(2,2-dimethylpropanoyl)-N-hydroxy-1-methyl-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-7-carboxamide I-2347-(biphenyl-4-ylcarbonyl)-N-hydroxy-8-methyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-2-carboxamide I-235N-hydroxy-7-{-3-[(pyrrolidin-3-ylamino)carbonyl]benzyl}-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-2-carboxamide I-236N-hydroxy-2-[(1-isopropylpiperidin-4-yl)methyl]-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-7-carboxamide I-237N-hydroxy-7-[(2-{[(4-methylpiperidin-4-yl)carbonyl]amino}pyridin-4-yl)methyl]-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-2-carboxamide I-238N-hydroxy-2-(4-{[(1-methylpiperidin-4-yl)carbonyl]amino}benzyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-7-carboxamide I-2392-[(1-ethylpiperidin-4-yl)methyl]-N-hydroxy-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-7-carboxamide I-240N-hydroxy-1-oxo-2-[4-(trifluoromethl)benzyl]-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-7-carboxamide I-2412-(cyclopropylmethyl)-N-hydroxy-1-oxo-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-7-carboxamide

3. General Synthetic Methods and Intermediates

The compounds of the present invention can be prepared by methods knownto one of ordinary skill in the art and/or by reference to the schemesshown below and the synthetic examples. Exemplary synthetic routes areset forth in Schemes below, and in the Examples.

Scheme 1 shows a general route for preparing compounds represented byformula vi. Starting from one of the following: diethyl1H-pyrrole-2,4-dicarboxylate (prepared as described by Bhattacharya etal., Tetrahedron Lett. 2006, 47(31):5481-5484);1H-1,2,4-triazole-3,5-dicarboxylic acid, 3,5-diethyl ester (commerciallyavailable); diethyl 3,5-pyrazoledicarboxylate (commercially available);or diethyl 5-amino-1H-imidazole-2,4-dicarboxylate (commerciallyavailable) compounds of formula v can be prepared in a sequenceanalogous to that described by Askew et al., Bioorg. Med. Chem. Lett.1995, 5(5):475.

Treatment of azole i with a dihaloalkane such as dibromoethane in thepresence of a base with heating (Method A; see also Pratt, et al.,Bioorg. Med. Chem. Lett. 2000, 10:2749) provides access to ii.Displacement of the pendant halide of ii with sodium azide (Method B,see Colombano et al., J. Med. Chem. 2010, 53: 616-623) affords iii whichupon application of reducing conditions such as a palladium metalcatalyst in a hydrogen atmosphere (Method C) provides access to thecorresponding primary amine iv. Primary amine iv can be cyclized withheating in the presence of base (Method D) to generate lactam v. Removalof the amide carbonyl is accomplished via reduction in the presence of asuitable hydride delivery agent such as BH₃.THF (Method E) as describedby Di Fabio et al., J. Med. Chem. 2009, 52:3238-3247.

Scheme 2 shows a general route for preparing compounds represented byformula xii. Sulfonamide viii can be prepared from the reaction ofpropargyl amine with o-nitrobenzene sulfonyl chloride (Method F).Alkylation of the sulfonamide can be effected upon treatment with adihaloalkane such as 1-bromo-2-chloroethane in the presence of a basesuch as cesium carbonate with heating (Method G). A 3+2 sigmatropiccyclization of the terminal acetylene with ethyl diazoacetate in asolvent such as benzene using a sealed tube with heating results in theconstruction of the pyrazole ring in compounds of formula x (Method H)in a fashion similar as described by Zrinski et al., Heterocycles 2006,68(9):1961. An intramolecular cyclization onto the pendant aliphaticchlorine with a pyrazole nitrogen can be achieved through additionalheating in the presence of a base such as cesium carbonate (Method I).Removal of the o-nitro sulfonamide protecting group is achieved bytreatment with thiophenol as described by Fukuyama et al., TetrahedronLett. 1995, 36(36):6373 (Method J). This route can also be employedusing substituted propargyl amines (racemic or optically pure) andsubstituted dihaloalkenes.

Scheme 3 shows a general route for the preparation of compounds of thetype represented by formula xviii. Racemic or optically pure isonitriles(xiii) prepared from the corresponding (3-amino acids (Sureshbabu etal., J. Org. Chem. 2009, 74:153) can be reacted with ethyl propiolate(xiv) to construct the pyrrole ring of xv through a 3+2 cycloaddition(Method K). Treatment of xv with a dihaloalkane such as dibromoethane inthe presence of a base with heating (Method A) affords xvi. Formation ofthe tetrahydropyrrolopyrazine ring system of xvii can be carried outthough the deprotonation of the carbamate nitrogen with sodium hydride,LDA or Cs₂CO₃ followed by cyclization onto the pendent bromide (MethodL; Yamaguchi et al., Chemistry Lett. 1996, 8:621). Removal of the Fmocprotecting group using piperidine (Method M) provides compounds offormula xviii.

Scheme 4 shows a general route for the preparation of substitutedcompounds of the type represented by formula xx. Racemic or opticallypure substituted 2-(aminomethyl)-1H-imidazole-4-carboxylate estersdepicted by xix (prepared as described by You et al., Organic Letters2004, 6:1681, can be converted to the tetrahydroimidazopyrazine xx(Methods A, L and M) in a fashion analogous to that depicted in Scheme3.

Scheme 5 shows a general route for the preparation of compounds of thetype represented by formula xxii. The Boc protecting group on7-tert-butyl 2-ethyl5,6-dihydro-[1,2,4]triazolo[1,5-a]pyrazine-2,7(8H)-dicarboxylate (xxi)(prepared as described by Carling et al., WO 00/023449) can be removedupon treatment with an acid such as HCl or TFA (Method N).

Scheme 6 shows a route for the preparation of substituted azolecompounds of formula xxv. Reaction of the secondary amines representedby compounds of formula xxiii with carboxylic acids (R³—CO₂H) employingcoupling agents such as HBTU or HATU leads to the formation of thecorresponding amide xiv (Method O). Conversion of the ethyl ester inxxiv to a hydroxamate is conducted by reaction with the potassium saltof hydroxylamine (Method P; Huang et al., J. Med. Chem. 2009,52(21):6757) leading to the formation of compounds of formula xxv.

Scheme 7 shows a route for the preparation of substituted azolecompounds of formula xxvii. Reaction of the secondary amine in compoundsrepresented by xxiii with sulfonyl chlorides (Method Q) leads to theformation of the corresponding sulfonamide xxvi. Conversion of xxvi tothe corresponding hydroxamate is carried out in an analogous fashion asshown in Scheme 6 (Method P) leading to the formation of compounds offormula xxvii.

Scheme 8 shows a route for the preparation of substituted azolecompounds of formula xxix. The reaction of the compounds of formulaxxiii with the isocyanates (R³—NCO; Method R) leads to the formation ofthe corresponding ureas of formula xxviii. Conversion of xxviii to thecorresponding hydroxamate is carried out in an analogous fashion asshown in Scheme 6 (Method P) leading to the formation of compounds offormula xxix.

Scheme 9 shows a route for the preparation of substituted azolecompounds of formula xxxi. Treatment of amine xxiii with either analdehyde under standard reductive amination conditions, (i.e. in thepresence of a borohydride such as sodium cyanoborohydride, Method S) oran alkyl halide in an S_(N)2 fashion (Method T) affords the tertiaryamine xxx. The secondary amine xxiii may also be arylated using standardnucleophilic aromatic substitution of a suitable eletrophile such as2-chloro-nitropyridine, in the presence of suitable base, such as DIPEAat elevated temperatures (Method U). Amine xxiii may also be N-arylatedthrough a copper(II)-acetate mediated coupling with a suitablearylboronic acid (Method V; Chan et al. Tetrahedron Lett. 1998,39(19):2933). Conversion of xxx to the corresponding hydroxamate iscarried out in an analogous fashion as shown in Scheme 6 (Method P)leading to the formation of compounds of formula xxxi.

4. Uses, Formulation and Administration

As discussed above, the present invention provides compounds andpharmaceutical compositions that are useful as inhibitors of HDACenzymes, particularly HDAC6, and thus the present compounds are usefulfor treating proliferative, inflammatory, infectious, neurological orcardiovascular disorders.

The compounds and pharmaceutical compositions of the invention areparticularly useful for the treatment of cancer. As used herein, theterm “cancer” refers to a cellular disorder characterized byuncontrolled or disregulated cell proliferation, decreased cellulardifferentiation, inappropriate ability to invade surrounding tissue,and/or ability to establish new growth at ectopic sites. The term“cancer” includes, but is not limited to, solid tumors and bloodbornetumors. The term “cancer” encompasses diseases of skin, tissues, organs,bone, cartilage, blood, and vessels. The term “cancer” furtherencompasses primary and metastatic cancers.

In some embodiments, therefore, the invention provides the compound offormula (I), or a pharmaceutically acceptable salt thereof, for use intreating cancer. In some embodiments, the invention provides apharmaceutical composition (as described herein) for the treatment ofcancer comprising the compound of formula (I), or a pharmaceuticallyacceptable salt thereof. In some embodiments, the invention provides theuse of the compound of formula (I), or a pharmaceutically acceptablesalt thereof, for the preparation of a pharmaceutical composition (asdescribed herein) for the treatment of cancer. In some embodiments, theinvention provides the use of an effective amount of the compound offormula (I), or a pharmaceutically acceptable salt thereof, for thetreatment of cancer.

Non-limiting examples of solid tumors that can be treated with thedisclosed inhibitors include pancreatic cancer; bladder cancer;colorectal cancer; breast cancer, including metastatic breast cancer;prostate cancer, including androgen-dependent and androgen-independentprostate cancer; renal cancer, including, e.g., metastatic renal cellcarcinoma; hepatocellular cancer; lung cancer, including, e.g.,non-small cell lung cancer (NSCLC), bronchioloalveolar carcinoma (BAC),and adenocarcinoma of the lung; ovarian cancer, including, e.g.,progressive epithelial or primary peritoneal cancer; cervical cancer;gastric cancer; esophageal cancer; head and neck cancer, including,e.g., squamous cell carcinoma of the head and neck; melanoma;neuroendocrine cancer, including metastatic neuroendocrine tumors; braintumors, including, e.g., glioma, anaplastic oligodendroglioma, adultglioblastoma multiforme, and adult anaplastic astrocytoma; bone cancer;and soft tissue sarcoma.

Non-limiting examples of hematologic malignancies that can be treatedwith the disclosed inhibitors include acute myeloid leukemia (AML);chronic myelogenous leukemia (CML), including accelerated CML and CMLblast phase (CML-BP); acute lymphoblastic leukemia (ALL); chroniclymphocytic leukemia (CLL); Hodgkin's disease (HD); non-Hodgkin'slymphoma (NHL), including follicular lymphoma and mantle cell lymphoma;B-cell lymphoma; T-cell lymphoma; multiple myeloma (MM); Waldenstrom'smacroglobulinemia; myelodysplastic syndromes (MDS), including refractoryanemia (RA), refractory anemia with ringed siderblasts (RARS),(refractory anemia with excess blasts (RAEB), and RAEB in transformation(RAEB-T); and myeloproliferative syndromes.

In some embodiments, compounds of the invention are suitable for thetreatment of breast cancer, lung cancer, ovarian cancer, multiplemyeloma, acute myeloid leukemia or acute lymphoblastic leukemia.

In other embodiments, compounds of the invention are suitable for thetreatment of inflammatory and cardiovascular disorders including, butnot limited to, allergies/anaphylaxis, acute and chronic inflammation,rheumatoid arthritis; autoimmunity disorders, thrombosis, hypertension,cardiac hypertrophy, and heart failure.

Accordingly, in another aspect of the present invention, pharmaceuticalcompositions are provided, wherein these compositions comprise any ofthe compounds as described herein, and optionally comprise apharmaceutically acceptable carrier, adjuvant or vehicle. In certainembodiments, these compositions optionally further comprise one or moreadditional therapeutic agents.

It will also be appreciated that certain of the compounds of presentinvention can exist in free form for treatment, or where appropriate, asa pharmaceutically acceptable derivative thereof. According to thepresent invention, a pharmaceutically acceptable derivative includes,but is not limited to, pharmaceutically acceptable prodrugs, salts,esters, salts of such esters, or any other adduct or derivative whichupon administration to a patient in need is capable of providing,directly or indirectly, a compound as otherwise described herein, or ametabolite or residue thereof.

As used herein, the term “pharmaceutically acceptable salt” refers tothose salts which are, within the scope of sound medical judgement,suitable for use in contact with the tissues of humans and lower animalswithout undue toxicity, irritation, allergic response and the like, andare commensurate with a reasonable benefit/risk ratio. A“pharmaceutically acceptable salt” means any non-toxic salt or salt ofan ester of a compound of this invention that, upon administration to arecipient, is capable of providing, either directly or indirectly, acompound of this invention or an inhibitorily active metabolite orresidue thereof. As used herein, the term “inhibitorily activemetabolite or residue thereof” means that a metabolite or residuethereof is also an inhibitor of HDAC6.

Pharmaceutically acceptable salts are well known in the art. Forexample, S. M. Berge et al., describe pharmaceutically acceptable saltsin detail in J Pharmaceutical Sciences, 1977, 66, 1-19, incorporatedherein by reference. Pharmaceutically acceptable salts of the compoundsof this invention include those derived from suitable inorganic andorganic acids and bases. Examples of pharmaceutically acceptable,nontoxic acid addition salts are salts of an amino group formed withinorganic acids such as hydrochloric acid, hydrobromic acid, phosphoricacid, sulfuric acid and perchloric acid or with organic acids such asacetic acid, oxalic acid, maleic acid, tartaric acid, citric acid,succinic acid or malonic acid or by using other methods used in the artsuch as ion exchange. Other pharmaceutically acceptable salts includeadipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate,bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate,cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate,formate, fumarate, glucoheptonate, glycerophosphate, gluconate,hemisulfate, heptanoate, hexanoate, hydroiodide,2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, laurylsulfate, malate, maleate, malonate, methanesulfonate,2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate,pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate,pivalate, propionate, stearate, succinate, sulfate, tartrate,thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and thelike. Salts derived from appropriate bases include alkali metal,alkaline earth metal, ammonium and N⁺(C₁₋₄alkyl)₄ salts. This inventionalso envisions the quaternization of any basic nitrogen-containinggroups of the compounds disclosed herein. Water or oil-soluble ordispersable products may be obtained by such quaternization.Representative alkali or alkaline earth metal salts include sodium,lithium, potassium, calcium, magnesium, and the like. Furtherpharmaceutically acceptable salts include, when appropriate, nontoxicammonium, quaternary ammonium, and amine cations formed usingcounterions such as halide, hydroxide, carboxylate, sulfate, phosphate,nitrate, loweralkyl sulfonate and aryl sulfonate.

As described above, the pharmaceutically acceptable compositions of thepresent invention additionally comprise a pharmaceutically acceptablecarrier, adjuvant, or vehicle, which, as used herein, includes any andall solvents, diluents, or other liquid vehicle, dispersion orsuspension aids, surface active agents, isotonic agents, thickening oremulsifying agents, preservatives, solid binders, lubricants and thelike, as suited to the particular dosage form desired. Remington'sPharmaceutical Sciences, Sixteenth Edition, E. W. Martin (MackPublishing Co., Easton, Pa., 1980) discloses various carriers used informulating pharmaceutically acceptable compositions and knowntechniques for the preparation thereof. Except insofar as anyconventional carrier medium is incompatible with the compounds of theinvention, such as by producing any undesirable biological effect orotherwise interacting in a deleterious manner with any othercomponent(s) of the pharmaceutically acceptable composition, its use iscontemplated to be within the scope of this invention. Some examples ofmaterials which can serve as pharmaceutically acceptable carriersinclude, but are not limited to, ion exchangers, alumina, aluminumstearate, lecithin, serum proteins, such as human serum albumin, buffersubstances such as phosphates, glycine, sorbic acid, or potassiumsorbate, partial glyceride mixtures of saturated vegetable fatty acids,water, salts or electrolytes, such as protamine sulfate, disodiumhydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zincsalts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone,polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, woolfat, sugars such as lactose, glucose and sucrose; starches such as cornstarch and potato starch; cellulose and its derivatives such as sodiumcarboxymethyl cellulose, ethyl cellulose and cellulose acetate; powderedtragacanth; malt; gelatin; talc; excipients such as cocoa butter andsuppository waxes; oils such as peanut oil, cottonseed oil; saffloweroil; sesame oil; olive oil; corn oil and soybean oil; glycols; such apropylene glycol or polyethylene glycol; esters such as ethyl oleate andethyl laurate; agar; buffering agents such as magnesium hydroxide andaluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline;Ringer's solution; ethyl alcohol, and phosphate buffer solutions, aswell as other non-toxic compatible lubricants such as sodium laurylsulfate and magnesium stearate, as well as coloring agents, releasingagents, coating agents, sweetening, flavoring and perfuming agents,preservatives and antioxidants can also be present in the composition,according to the judgment of the formulator.

In yet another aspect, a method for treating a proliferative,inflammatory, infectious, neurological or cardiovascular disorder isprovided comprising administering an effective amount of a compound, ora pharmaceutical composition to a subject in need thereof. In certainembodiments of the present invention an “effective amount” of thecompound or pharmaceutical composition is that amount effective fortreating a proliferative, inflammatory, infectious, neurological orcardiovascular disorder, or is that amount effective for treatingcancer. In other embodiments, an “effective amount” of a compound is anamount which inhibits binding of HDAC6, and thereby blocks the resultingsignaling cascades that lead to the abnormal activity of growth factors,receptor tyrosine kinases, protein serine/threonine kinases, G proteincoupled receptors and phospholipid kinases and phosphatases.

The compounds and compositions, according to the method of the presentinvention, may be administered using any amount and any route ofadministration effective for treating the disease. The exact amountrequired will vary from subject to subject, depending on the species,age, and general condition of the subject, the severity of theinfection, the particular agent, its mode of administration, and thelike. The compounds of the invention are preferably formulated in dosageunit form for ease of administration and uniformity of dosage. Theexpression “dosage unit form” as used herein refers to a physicallydiscrete unit of agent appropriate for the patient to be treated. Itwill be understood, however, that the total daily usage of the compoundsand compositions of the present invention will be decided by theattending physician within the scope of sound medical judgment. Thespecific effective dose level for any particular patient or organismwill depend upon a variety of factors including the disease beingtreated and the severity of the disease; the activity of the specificcompound employed; the specific composition employed; the age, bodyweight, general health, sex and diet of the patient; the time ofadministration, route of administration, and rate of excretion of thespecific compound employed; the duration of the treatment; drugs used incombination or coincidental with the specific compound employed, andlike factors well known in the medical arts. The term “patient”, as usedherein, means an animal, preferably a mammal, and most preferably ahuman.

The pharmaceutically acceptable compositions of this invention can beadministered to humans and other animals orally, rectally, parenterally,intracisternally, intravaginally, intraperitoneally, topically (as bypowders, ointments, or drops), bucally, as an oral or nasal spray, orthe like, depending on the severity of the infection being treated. Incertain embodiments, the compounds of the invention may be administeredorally or parenterally at dosage levels of about 0.01 mg/kg to about 50mg/kg and preferably from about 1 mg/kg to about 25 mg/kg, of subjectbody weight per day, one or more times a day, to obtain the desiredtherapeutic effect.

Liquid dosage forms for oral administration include, but are not limitedto, pharmaceutically acceptable emulsions, microemulsions, solutions,suspensions, syrups and elixirs. In addition to the active compounds,the liquid dosage forms may contain inert diluents commonly used in theart such as, for example, water or other solvents, solubilizing agentsand emulsifiers such as ethyl alcohol, isopropyl alcohol, ethylcarbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propyleneglycol, 1,3-butylene glycol, dimethylformamide, oils (in particular,cottonseed, groundnut, corn, germ, olive, castor, and sesame oils),glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fattyacid esters of sorbitan, and mixtures thereof. Besides inert diluents,the oral compositions can also include adjuvants such as wetting agents,emulsifying and suspending agents, sweetening, flavoring, and perfumingagents.

Injectable preparations, for example, sterile injectable aqueous oroleaginous suspensions may be formulated according to the known artusing suitable dispersing or wetting agents and suspending agents. Thesterile injectable preparation may also be a sterile injectablesolution, suspension or emulsion in a nontoxic parenterally acceptablediluent or solvent, for example, as a solution in 1,3-butanediol. Amongthe acceptable vehicles and solvents that may be employed are water,Ringer's solution, U.S.P. and isotonic sodium chloride solution. Inaddition, sterile, fixed oils are conventionally employed as a solventor suspending medium. For this purpose any bland fixed oil can beemployed including synthetic mono- or diglycerides. In addition, fattyacids such as oleic acid are used in the preparation of injectables.

The injectable formulations can be sterilized, for example, byfiltration through a bacterial-retaining filter, or by incorporatingsterilizing agents in the form of sterile solid compositions which canbe dissolved or dispersed in sterile water or other sterile injectablemedium prior to use.

In order to prolong the effect of a compound of the present invention,it is often desirable to slow the absorption of the compound fromsubcutaneous or intramuscular injection. This may be accomplished by theuse of a liquid suspension of crystalline or amorphous material withpoor water solubility. The rate of absorption of the compound thendepends upon its rate of dissolution that, in turn, may depend uponcrystal size and crystalline form. Alternatively, delayed absorption ofa parenterally administered compound form is accomplished by dissolvingor suspending the compound in an oil vehicle. Injectable depot forms aremade by forming microencapsule matrices of the compound in biodegradablepolymers such as polylactide-polyglycolide. Depending upon the ratio ofcompound to polymer and the nature of the particular polymer employed,the rate of compound release can be controlled. Examples of otherbiodegradable polymers include poly(orthoesters) and poly(anhydrides).Depot injectable formulations are also prepared by entrapping thecompound in liposomes or microemulsions that are compatible with bodytissues.

Compositions for rectal or vaginal administration are preferablysuppositories which can be prepared by mixing the compounds of thisinvention with suitable non-irritating excipients or carriers such ascocoa butter, polyethylene glycol or a suppository wax which are solidat ambient temperature but liquid at body temperature and therefore meltin the rectum or vaginal cavity and release the active compound.

Solid dosage forms for oral administration include capsules, tablets,pills, powders, and granules. In such solid dosage forms, the activecompound is mixed with at least one inert, pharmaceutically acceptableexcipient or carrier such as sodium citrate or dicalcium phosphateand/or a) fillers or extenders such as starches, lactose, sucrose,glucose, mannitol, and silicic acid, b) binders such as, for example,carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone,sucrose, and acacia, c) humectants such as glycerol, d) disintegratingagents such as agar-agar, calcium carbonate, potato or tapioca starch,alginic acid, certain silicates, and sodium carbonate, e) solutionretarding agents such as paraffin, f) absorption accelerators such asquaternary ammonium compounds, g) wetting agents such as, for example,cetyl alcohol and glycerol monostearate, h) absorbents such as kaolinand bentonite clay, and i) lubricants such as talc, calcium stearate,magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate,and mixtures thereof. In the case of capsules, tablets and pills, thedosage form may also comprise buffering agents.

Solid compositions of a similar type may also be employed as fillers insoft and hard-filled gelatin capsules using such excipients as lactoseor milk sugar as well as high molecular weight polyethylene glycols andthe like. The solid dosage forms of tablets, dragees, capsules, pills,and granules can be prepared with coatings and shells such as entericcoatings and other coatings well known in the pharmaceutical formulatingart. They may optionally contain opacifying agents and can also be of acomposition that they release the active ingredient(s) only, orpreferentially, in a certain part of the intestinal tract, optionally,in a delayed manner. Examples of embedding compositions that can be usedinclude polymeric substances and waxes. Solid compositions of a similartype may also be employed as fillers in soft and hard-filled gelatincapsules using such excipients as lactose or milk sugar as well as highmolecular weight polethylene glycols and the like.

The active compounds can also be in micro-encapsulated form with one ormore excipients as noted above. The solid dosage forms of tablets,dragees, capsules, pills, and granules can be prepared with coatings andshells such as enteric coatings, release controlling coatings and othercoatings well known in the pharmaceutical formulating art. In such soliddosage forms the active compound may be admixed with at least one inertdiluent such as sucrose, lactose or starch. Such dosage forms may alsocomprise, as is normal practice, additional substances other than inertdiluents, e.g., tableting lubricants and other tableting aids such amagnesium stearate and microcrystalline cellulose. In the case ofcapsules, tablets and pills, the dosage forms may also comprisebuffering agents. They may optionally contain opacifying agents and canalso be of a composition that they release the active ingredient(s)only, or preferentially, in a certain part of the intestinal tract,optionally, in a delayed manner. Examples of embedding compositions thatcan be used include polymeric substances and waxes.

Dosage forms for topical or transdermal administration of a compound ofthis invention include ointments, pastes, creams, lotions, gels,powders, solutions, sprays, inhalants or patches. The active componentis admixed under sterile conditions with a pharmaceutically acceptablecarrier and any needed preservatives or buffers as may be required.Ophthalmic formulation, ear drops, and eye drops are also contemplatedas being within the scope of this invention. Additionally, the presentinvention contemplates the use of transdermal patches, which have theadded advantage of providing controlled delivery of a compound to thebody. Such dosage forms can be made by dissolving or dispensing thecompound in the proper medium. Absorption enhancers can also be used toincrease the flux of the compound across the skin. The rate can becontrolled by either providing a rate controlling membrane or bydispersing the compound in a polymer matrix or gel.

In some embodiments, a compound of formula (I) or a pharmaceuticalcomposition thereof is administered in conjunction with an anticanceragent. As used herein, the term “anticancer agent” refers to any agentthat is administered to a subject with cancer for purposes of treatingthe cancer. Combination therapy includes administration of thetherapeutic agents concurrently or sequentially. Alternatively, thetherapeutic agents can be combined into one composition which isadministered to the patient.

Non-limiting examples of DNA damaging chemotherapeutic agents includetopoisomerase I inhibitors (e.g., irinotecan, topotecan, camptothecinand analogs or metabolites thereof, and doxorubicin); topoisomerase IIinhibitors (e.g., etoposide, teniposide, and daunorubicin); alkylatingagents (e.g., melphalan, chlorambucil, busulfan, thiotepa, ifosfamide,carmustine, lomustine, semustine, streptozocin, decarbazine,methotrexate, mitomycin C, and cyclophosphamide); DNA intercalators(e.g., cisplatin, oxaliplatin, and carboplatin); DNA intercalators andfree radical generators such as bleomycin; and nucleoside mimetics(e.g., 5-fluorouracil, capecitibine, gemcitabine, fludarabine,cytarabine, mercaptopurine, thioguanine, pentostatin, and hydroxyurea).

Chemotherapeutic agents that disrupt cell replication include:paclitaxel, docetaxel, and related analogs; vincristine, vinblastin, andrelated analogs; thalidomide, lenalidomide, and related analogs (e.g.,CC-5013 and CC-4047); protein tyrosine kinase inhibitors (e.g., imatinibmesylate and gefitinib); proteasome inhibitors (e.g., bortezomib); NF-κBinhibitors, including inhibitors of IκB kinase; antibodies which bind toproteins overexpressed in cancers and thereby downregulate cellreplication (e.g., trastuzumab, rituximab, cetuximab, and bevacizumab);and other inhibitors of proteins or enzymes known to be upregulated,over-expressed or activated in cancers, the inhibition of whichdown-regulates cell replication. In certain embodiments, a compound ofthe invention is administered in conjunction with a proteasomeinhibitor.

Another aspect of the invention relates to inhibiting HDAC6, activity ina biological sample or a patient, which method comprises administeringto the patient, or contacting said biological sample with a compound offormula (I), or a composition comprising said compound. The term“biological sample”, as used herein, generally includes in vivo, invitro, and ex vivo materials, and also includes, without limitation,cell cultures or extracts thereof; biopsied material obtained from amammal or extracts thereof; and blood, saliva, urine, feces, semen,tears, or other body fluids or extracts thereof.

Still another aspect of this invention is to provide a kit comprisingseparate containers in a single package, wherein the inventivepharmaceutical compounds, compositions and/or salts thereof are used incombination with pharmaceutically acceptable carriers to treatdisorders, symptoms and diseases where HDAC6 plays a role.

5. Preparation of Exemplary Compounds EXPERIMENTAL PROCEDURESDefinitions

-   ATP adenosine triphosphate-   DCE dichloroethane-   DCM dichloromethane-   DIPEA diisopropylethyl amine-   DMF N,N-dimethylformamide-   DMFDMA N,N-dimethylformamide dimethyl acetal-   DMSO dimethylsulfoxide-   EDCI N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride-   EDTA ethylenediaminetetraacetic acid-   EtOAc ethyl acetate-   EtOH ethanol-   FA formic acid-   FBS fetal bovine serum-   Fmoc 9H-fluoren-9-ylmethoxycarbonyl-   h hours-   HATU N,N, N′,N′-tetramethyl-o-(7-azabenzotriazole-1-yl)uronium    hexafluorophosphate-   HBTU o-benzotriazol-1-yl-N,N, N′,N′-tetramethyluronium    hexafluorophosphate-   HEPES N-(2-hydroxyethyl)piperazine-N′-(2-ethanesulfonic acid)-   HOBT 1-hydroxybenztriazole hydrate-   HRMS high resolution mass spectrum-   IPA isopropyl alcohol-   LAH lithium aluminum hydride-   LC-MS liquid chromatography mass spectrum-   m/z mass to charge-   MTBE methyl tert-butyl ether-   Me methyl-   MeCN acetonitrile-   MEM minimum essential media-   MeOH methanol-   min minutes-   MS mass spectrum-   MWI microwave irradiation-   NMM N-methyl morpholine-   PBS phosphate buffered saline-   rt room temperature-   TEA triethylamine-   TFA trifluoroacetic acid-   TFAA trifluoroacetic anhydride-   TFFH tetramethylfluoroformamidinium hexafluorophosphate-   THF tetrahydrofuran-   THP tetrahydropyranyl

Analytical Methods

NMR: ¹H NMR spectra are run on a 400 MHz Bruker unless otherwise stated.

LCMS: LC-MS spectra are run using an Agilent 1100 LC interfaced to amicromass Waters® Micromass® Zspray™ Mass Detector (ZMD).

HPLC: Preparative HPLC are conducted using 18×150 mm Sunfire C-18columns eluting with water-MeCN gradients using a Gilson instrumentoperated by 322 pumps with the UV/visible 155 detector triggeredfraction collection set to between 200 nm and 400 nm. Mass gatedfraction collection is conducted on an Agilent 1100 LC/MSD instrument.

Example 1 ethyl 1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-7-carboxylate2,2,2-trifluoroacetate Intermediate 5

Step 1: diethyl 1H-pyrrole-2,4-dicarboxylate Intermediate 1

A suspension of potassium hydride (0.53 g, 13.26 mmol) in MTBE (10 mL)was added to a stirred solution of ethyl 2-isocyanoacetate (1 g, 8.84mmol) and ethyl propiolate (1 g, 10.19 mmol) in MTBE (10 mL). Theresulting mixture was stirred at rt for 4 h. The solution was thenacidified with 1N HCl to pH≦3. The organic layer was washed with sat.NaHCO₃ solution (2 mL), brine (2 mL), dried (MgSO₄), and concentrated togive a solid residue. Purification via flash chromatography (petroleumether:EtOAc, 15:1 to 10:1) afforded diethyl 1H-pyrrole-2,4-dicarboxylate(0.7 g, 37%). ¹H NMR (CDCl₃, 300 MHz) δ9.75 (br, 1H), 7.49 (s, 1H), 7.24(s, 1H), 4.25 (m, 4H), 1.29 (m, 6H).

Step 2: diethyl 1-(2-bromoethyl)-1H-pyrrole-2,4-dicarboxylateIntermediate 2

To a stirred solution of diethyl 1H-pyrrole-2,4-dicarboxylate (0.7 g,3.31 mmol), and 1,2-dibromoethane (2.8 mL, 32.5 mmol) in MeCN (30 mL)was added K₂CO₃ (0.55 g, 39.7 mmol). This reaction mixture was refluxedovernight then filtered. The filtrate was collected and concentrated togive diethyl 1-(2-bromoethyl)-1H-pyrrole-2,4-dicarboxylate (0.8 g, 76%).¹H NMR (CDCl₃, 300 MHz) δ7.42 (d, J=1.8 Hz, 1H), 7.33 (d, J=1.8 Hz, 1H),4.60 (t, J=6.0 Hz, 2H), 4.22 (q, J=7.2 Hz, 4H), 3.62 (t, J=6.4 Hz, 2H),1.28 (m, 6H).

Step 3: diethyl 1-(2-azidoethyl)-1H-pyrrole-2,4-dicarboxylateIntermediate 3

To a solution of diethyl 1-(2-bromoethyl)-1H-pyrrole-2,4-dicarboxylate(0.8 g) in DMF (10 mL) was added sodium azide (0.2 g, 3.07 mmol). Theresulting mixture was stirred at rt overnight then diluted with water(10 mL) and EtOAc (100 mL). After separation, the aqueous layer wasextracted with EtOAc (2×50 mL). The combined organic layers were washedwith brine, dried (MgSO₄) and concentrated. Purification via flashchromatography (petroleum ether:EtOAc, 20:1 to 15:1) afforded diethyl1-(2-azidoethyl)-1H-pyrrole-2,4-dicarboxylate (0.4 g, 57%). ¹H NMR(CDCl₃, 300 MHz) δ7.49 (d, J=1.8 Hz, 1H), 7.43 (d, J=1.8 Hz, 1H), 4.88(t, J=5.5 Hz, 2H), 4.32 (q, J=7.2 Hz, 4H), 3.70 (t, J=6.4 Hz, 2H), 1.38(m, 6H).

Step 4: ethyl1-oxo-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-7-carboxylateIntermediate 4

To a solution of diethyl 1-(2-azidoethyl)-1H-pyrrole-2,4-dicarboxylate(10 g, 35.68 mmol) in EtOH (1000 mL) was added 10% Pd/C (3 g). Theresulting residue was stirred at rt under a 30 psi H₂ atmosphere for 2h. The palladium catalyst was filtered. To the filtrate was addedpotassium carbonate (5 g, 36 mmol) and the mixture was refluxedovernight. All solids were removed by filtration, and the filtrate wasconcentrated. Purification via flash chromatography (DCM: methanol, 50:1to 20:1) afforded ethyl1-oxo-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-7-carboxylate (2.5 g,41%). ¹H NMR (DMSO-d₆, 300 MHz) δ7.91 (s, 1H), 7.64 (s, 1H), 6.90 (s,1H), 4.18 (m, 4H), 3.50 (m, 2H), 1.25 (t, J=5.4 Hz, 3 H).

Step 5: ethyl 1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-7-carboxylate2,2,2-trifluoroacetate Intermediate 5

To a solution of ethyl1-oxo-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-7-carboxylate (5 g, 24mmol) in THF (1000 mL) was added sodium borohydride (40 g, 1.05 mol)under nitrogen. The mixture was cooled to 0° C. and boron trifluorideetherate (200 mL, 1.59 mmol) was added dropwise. The reaction mixturewas stirred overnight at rt then EtOH (500 mL) was added. The solventwas then evaporated. To the resulting residue was added EtOH (850 mL),water (150 mL), and 10% aqueous HCl (75 mL). After the solution wasstirred at rt for 4 h, the EtOH was removed by evaporation. Theresulting solution was neutralized with sat. NaHCO₃ solution to pH≧8then diluted with EtOAc (500 mL). After separation, the aqueous layerwas extracted with EtOAc (2×500 mL). The combined organic layers wereconcentrated. Purification via prep-HPLC afforded ethyl1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-7-carboxylate2,2,2-trifluoroacetate (3.1 g, 26%) as a solid. ¹H NMR (DMSO-d₆, 300MHz) δ9.34 (s, 1H), 7.47 (s, 1H), 6.34 (s, 1H), 4.29 (s, 2H), 4.15 (m,4H), 3.54 (m, 2H), 1.21 (t, J=7.1 Hz, 3H).

Example 2 ethyl2,3,4,5-tetrahydro-1H-pyrrolo[1,2-a][1,4]diazepine-8-carboxylate2,2,2-trifluoroacetate Intermediate 9

Step 1: diethyl 1-(3-bromopropyl)-1H-pyrrole-2,4-dicarboxylateIntermediate 6

To a stirred solution of diethyl 1H-pyrrole-2,4-dicarboxylate (2 g, 9.47mmol) and 1,3-dibromopropane (10 mL, 98 mmol) in acetonitrile was addedpotassium carbonate (1.7 g, 12.3 mmol). The mixture was refluxedovernight, then filtered and concentrated to give crude diethyl1-(3-bromopropyl)-1H-pyrrole-2,4-dicarboxylate. ¹H NMR (CDCl₃, 300 MHz)δ7.47 (s, 1H), 7.36 (s, 1H), 4.47 (t, J=6.6 Hz, 2H), 4.27 (m, 4H), 3.32(t, J=6.2 Hz, 2H), 2.32 (m, 2H), 1.34 (m, 6H).

Step 2: diethyl 1-(3-azidopropyl)-1H-pyrrole-2,4-dicarboxylateIntermediate 7

To a stirred solution of crude diethyl1-(3-bromopropyl)-1H-pyrrole-2,4-dicarboxylate in DMF (30 mL) was addedsodium azide (1 g, 15.4 mmol). The resulting mixture was stirred at rtovernight then diluted with water (30 mL) and EtOAc (150 mL). Afterseparation, the aqueous layer was extracted with EtOAc (2×150 mL). Thecombined organic layers were washed with brine, dried (MgSO₄), andconcentrated. Purification via flash chromatography (petroleumether:EtOAc, 20:1 to 15:1) afforded diethyl1-(3-azidopropyl)-1H-pyrrole-2,4-dicarboxylate (2 g, 75%). ¹H NMR(CDCl₃, 300 MHz) δ7.42 (s, 1H), 7.36 (s, 1H), 4.40 (t, J=6.6 Hz, 2H),4.26 (m, 4H), 3.30 (m, J=6.2 Hz, 2H), 2.04 (m, 2H), 1.36 (m, 6H).

Step 3: ethyl1-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[1,2-a][1,4]diazepine-8-carboxylateIntermediate

To a solution of diethyl 1-(3-azidopropyl)-1H-pyrrole-2,4-dicarboxylateIntermediate 7 (8 g, 27.2 mmol) in EtOH (800 mL) was added 10% Pd/C (2g). The reaction was stirred at rt under a 30 psi H₂ atmosphere for 2 hthen filtered. To the filtrate was added potassium carbonate (4 g, 28.9mmol). The reaction was then refluxed overnight. All the solids werethen removed by filtration and the filtrate was then concentrated togive a solid which was dissolved in DCM (200 mL) and 1N aqueous HCl.After separation, the aqueous layer was extracted with DCM (2×150 mL).The combined organic layers were washed with brine, dried (MgSO₄), andconcentrated to give ethyl1-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[1,2-a][1,4]diazepine-8-carboxylate(4 g, 66%). ¹H NMR (DMSO-d₆, 300 MHz) δ7.88 (s, 1H), 7.61 (s, 1H), 6.84(s, 1H), 4.19 (m, 4H), 3.09 (m, 2H), 1.99 (m, 2H), 1.25 (t, J=7.1 Hz,3H).

Step 4: ethyl2,3,4,5-tetrahydro-1H-pyrrolo[1,2-a][1,4]diazepine-8-carboxylate2,2,2-trifluoroacetate Intermediate 9

To a solution of ethyl1-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[1,2-a][1,4]diazepine-8-carboxylate(4 g, 18 mmol) in THF (800 mL) was added sodium borohydride (32 g, 0.84mol) under nitrogen. The mixture was cooled to 0° C. and borontrifluoride etherate (160 mL, 1.27 mmol) was added dropwise. Thereaction mixture was stirred at rt overnight then EtOH (700 mL) wasslowly added. The solvent was evaporated and to the resulting residuewas added EtOH (1000 mL), water (240 mL), and 10% aqueous HCl (120 mL).After stirring at rt for 4 h, the EtOH was removed by evaporation. Theremaining solution was neutralized with sat. NaHCO₃ solution to a pH of≧8 and then diluted with EtOAc (500 mL). After separation, the aqueouslayer was extracted with EtOAc (2×500 mL). The combined organic layerswere concentrated. The residue obtained was dissolved in DMSO (1 mL) andpurified via prep-HPLC afforded ethyl2,3,4,5-tetrahydro-1H-pyrrolo[1,2-a][1,4]diazepine-8-carboxylate2,2,2-trifluoroacetate (1.91 g, 33%) as a solid. ¹H NMR (DMSO-d₆, 300MHz) δ8.94 (s, 2H), 7.51 (s, 1 H), 6.54 (s, 1H), 4.28 (s, 2H), 4.19 (m,2H), 4.12 (q, J=7.1 Hz, 2H), 3.28 (m, 2H), 1.92 (m, 2H), 1.19 (t, J=7.1Hz, 3H).

Example 32-[1-adamantylcarbonyl]-N-hydroxy-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-7-carboxamideCompound I-62

Step 1: ethyl2-(1-adamantylcarbonyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-7-carboxylateIntermediate 10

To a microwave vial containing 1-adamantanecarboxylic acid (0.05 g,0.283 mmol) was added HATU (0.11 g, 0.283 mmol), triethylamine (0.11 mL,0.772 mmol) and DMF (1.5 mL). The solution was allowed to stir at rt for30 minutes before ethyl1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-7-carboxylate Intermediate 5(0.05 g, 0.257 mmol) was added to the solution. The solution was thenallowed to stir at rt overnight and then evaporated. To the resultingresidue was added DCE (3 mL) and water (1 mL). After separation, theaqueous phase was extracted with DCE (2×3 mL). The combined organicphases were concentrated to give a crude ethyl2-(1-adamantylcarbonyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-7-carboxylateas a solid.

Step 2:2-(1-adamantylcarbonyl)-N-hydroxy-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-7-carboxamideCompound I-62

To a vial with crude ethyl2-(1-adamantylcarbonyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-7-carboxylatefrom Step 1 was added potassium hydroxide (0.145 g, 2.59 mmol),hydroxylamine hydrochloride (0.054 g, 0.776 mmol), and methanol (1.63mL). The vial was capped, heated at 80° C. for 1 h, and then cooled tort. Acetic acid (0.147 mL, 2.59 mmol) was slowly added to the solutionto quench the excess base and then the solvent was completelyevaporated. To the resulting residue was added DMSO (1.2 mL). Thesolution was purified by prep-HPLC purification after filtration to givethe title compound (0.0011 g, 1.2%) as a white solid. LC-MS: (FA)ES+344; ¹H NMR (CDCl₃, 300 MHz) δ7.21 (s, 1H), 6.36 (s, 1H), 4.85 (s,2H), 4.00 (m, 2H), 3.79 (m, 2H), 2.10-1.60 (m, 15H).

Example 4

The following compounds were prepared in an analogous fashion to thatdescribed in Example 3 starting from the intermediates which wereprepared as described above and the corresponding carboxylic acids.

LC-MS Compound (FA) I-20 ES+ 339 I-47 ES+ 368 I-73 ES+ 307 I-64 ES− 418I-85 ES+ 304 I-39 ES+ 290 I-66 ES+ 344 I-30 ES+ 292 I-58 ES+ 339 I-89ES+ 339 I-15 ES+ 345 I-51 ES+ 362 I-10 ES+ 342 I-84 ES+ 327 I-68 ES+ 316I-28 ES+ 353 I-3 ES+ 326 I-94 ES+ 303 I-1 ES+ 342 I-54 ES+ 364 I-61 ES+305 I-35 ES+ 399 I-22 ES+ 339 I-82 ES+ 381 I-75 ES+ 325 I-87 ES+ 441I-52 ES+ 304 I-40 ES+ 303 I-29 ES+ 325 I-91 ES+ 357 I-99 ES+ 366 I-92ES+ 292 I-32 ES+ 289

Example 52-butyl-N-hydroxy-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-7-carboxamideCompound I-86

Step 1: ethyl2-butyl-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-7-carboxylateIntermediate 11

To a solution of ethyl1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-7-carboxylate trifluoroacetate(2.6 g, 13.4 mmol) and 1-bromobutane (3.67 g, 26.8 mmol) in acetonitrile(26 mL) was added potassium carbonate (2.45 g, 17.7 mmol). The resultingmixture was refluxed overnight. The solvent was then evaporated to givea solid residue. Purification via flash chromatography (petroleumether:EtOAc, 10:1) afforded ethyl2-butyl-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-7-carboxylateIntermediate 11 (0.7 g, 21%). ¹H NMR (CDCl₃, 300 MHz) δ7.11 (s, 1H),6.18 (s, 1H), 4.25 (m, 2H), 3.99 (m, 2H), 3.53 (s, 2H), 2.82 (t, J=5.6Hz, 2H), 2.46 (t, J=7.4 Hz, 2H), 1.46 (m, 2H), 1.30 (m, 2 H), 1.25 (t,J=7.1 Hz, 3H), 0.87 (t, J=7.3 Hz, 2H).

Step 2:2-butyl-N-hydroxy-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-7-carboxamideCompound I-86

To a vial was added ethyl2-butyl-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-7-carboxylateIntermediate 11 (0.075 g, 0.3 mmol), hydroxylamine hydrochloride (0.084g, 1.2 mmol), potassium hydroxide (0.135 g, 2.4 mmol), and methanol (3mL). The vial was capped and heated at 80° C. for 1 h. Upon cooling tort, acetic acid (0.068 mL, 1.2 mmol) was added to neutralize the excessbase. The solvent was then removed and to the resulting residue wasadded DMSO (1.2 mL). The solution was filtered and purified by Gilsonprep-HPLC to give the title compound (0.0176 g, 25%) as a white solid.LC-MS: (FA) ES+238; ¹H NMR (Methanol-d₄, 400 MHz) δ 7.45 (d, J=1.55 Hz,1H), 6.49 (s, 1H), 4.50 (m, 2H), 4.37 (t, J=5.8 Hz, 2H), 3.79 (m, 2H),3.77 (s, 2H), 1.81 (m, 2H), 1.46 (m, 2H), 1.02 (t, J=7.3 Hz, 3H).

Example 62-benzyl-N-hydroxy-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-7-carboxamideCompound I-23

The title compound was prepared in an analogous fashion to thatdescribed in Example 5 starting from the appropriate starting materials.Yield: 61%. LC-MS (FA): ES+272.

Example 72-benzyl-N-hydroxy-1-oxo-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-7-carboxamideCompound I-42

Step 1: ethyl2-benzyl-1-oxo-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-7-carboxylateIntermediate

To a vial charged with ethyl1-oxo-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-7-carboxylate (0.0298 g,0.143 mmol) was added cesium carbonate (0.061 g, 0.186 mmol), benzylbromide (0.037 g, 0.2145 mmol), and acetonitrile (1 mL). The vial wascapped and was shaken at 70° C. overnight. The solids were removed byfiltration and the solution was concentrated to give crude ethyl2-benzyl-1-oxo-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-7-carboxylateIntermediate 12.

Step 2:2-benzyl-N-hydroxy-1-oxo-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-7-carboxamideCompound I-42

To a vial was added potassium hydroxide (0.1 g, 2 mmol), hydroxylaminehydrochloride (0.05 g, 0.715 mmol), and DMSO (1 mL). The vial wassonicated until the hydroxylamine hydrochloride had gone into solution.This solution was then added to the vial containing the crude ethyl2-benzyl-1-oxo-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-7-carboxylateprepared in Step 1 above. The resulting mixture was shaken overnight atroom temperature. Purification via Gilson prep-HPLC afforded2-benzyl-N-hydroxy-1-oxo-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-7-carboxamide(0.0049 g, 11.7%). LC-MS: (FA) ES+286; ¹H NMR (Methanol-d₄, 400 MHz)δ7.39 (s, 1H), (m, 5H), 7.15 (s, 1 H), 4.74 (s, 2H), 3.64 (t, J=5.8 Hz,2H), 4.18 (t, J=6.0 Hz, 2H).

Example 82-benzyl-N-hydroxy-1-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[1,2-a][1,4]diazepine-8-carboxamideCompound I-49

The title compound was prepared in an analogous fashion to thatdescribed in Example 7 starting from the appropriate starting materials.Yield: 9.5%. LC-MS (FA): ES+300; ¹H NMR (Methanol-d₄, 400 MHz)δ7.40-7.28 (m, 6H), 7.01 (s, 1H), 4.72 (s, 2H), 4.14 (t, J=6.8 Hz, 2H),3.35 (t, J=6.5 Hz, 2H), 1.95 (m, 2H).

Example 9N-hydroxy-2-(1-methyl-1H-pyrrole-2-carbonyl)-2,3,4,5-tetrahydro-1H-pyrrolo[1,2-a][1,4]diazepine-8-carboxamideCompound I-9

Step 1: ethyl2-(1-methyl-1H-pyrrole-2-carbonyl)-2,3,4,5-tetrahydro-1H-pyrrolo[1,2-a][1,4]diazepine-8-carboxylateIntermediate 13

To a vial containing N-methylpyrrole-2-carboxylic acid (0.025 g, 0.2mmol) was added HATU (0.076 g, 0.2 mmol), DCM (2 mL), and triethylamine(0.112 mL, 0.8 mmol). The solution was stirred at rt for 30 min thenethyl 2,3,4,5-tetrahydro-1H-pyrrolo[1,2-a][1,4]diazepine-8-carboxylate2,2,2-trifluoroacetate (0.0644 g, 0.2 mmol) in DMF (0.5 mL) was added.The mixture was stirred at rt for 2 h. The reaction was quenched byaddition of DCM (1 mL), sat. NaHCO₃ solution (0.5 mL), and water (1 mL).After separation, the aqueous layer was extracted with DCE (2×3 mL). Thecombined organic layers were concentrated to give crude ethyl2-(1-methyl-1H-pyrrole-2-carbonyl)-2,3,4,5-tetrahydro-1H-pyrrolo[1,2-a][1,4]diazepine-8-carboxylate.

Step 2:N-hydroxy-2-(1-methyl-1H-pyrrole-2-carbonyl)-2,3,4,5-tetrahydro-1H-pyrrolo[1,2-a][1,4]diazepine-8-carboxamideCompound I-9

To a vial containing crude ethyl2-(1-methyl-1H-pyrrole-2-carbonyl)-2,3,4,5-tetrahydro-1H-pyrrolo[1,2-a][1,4]diazepine-8-carboxylatefrom Step 1 above was added potassium hydroxide (0.112 g, 2 mmol),hydroxylamine hydrochloride (0.0417 g, 0.6 mmol), and methanol (2 mL).The mixture was shaken at 80° C. for 2 h then cooled to roomtemperature. Acetic acid (0.114 mL, 2 mmol) was added to quench theexcess base. The solvent was then completely evaporated and to theresidue was added DMSO (1.2 mL). After filtration, the solution waspurified via Gilson prep-HPLC to giveN-hydroxy-2-(1-methyl-1H-pyrrole-2-carbonyl)-2,3,4,5-tetrahydro-1H-pyrrolo[1,2-a][1,4]diazepine-8-carboxamide(0.004 g, 6.5%). LC-MS (FA): ES+303; ¹H NMR (CD₃CN, 400 MHz) δ6.81 (s,1H), 6.40 (s, 1H), 5.95 (m, 1H), 5.81 (m, 1H), 5.70 (m, 1H), 4.27 (s,2H), 3.83 (m, 2H), 3.51 (m, 2H), 3.21 (s, 3H), 1.85 (m, 2H).

Example 10

The following compounds were prepared in an analogous fashion to thatdescribed in Example 9 starting from the intermediates which wereprepared as described above and the corresponding carboxylic acids.

LC-MS Compound (FA) I-7 ES+ 380 I-19 ES+ 292 I-74 ES+ 320 I-79 ES+ 368I-95 ES+ 332 I-56 ES+ 334 I-18 ES+ 356 I-69 ES+ 320 I-43 ES+ 314 I-33ES− 366 I-104 ES+ 371 I-65 ES+ 360 I-5 ES− 485 I-96 ES+ 356 I-25 ES+ 351I-111 ES+ 306 I-78 ES+ 321 I-34 ES+ 374 I-59 ES+ 294 I-34 ES+ 358 I-80ES+ 390 I-4 ES+ 318

Example 11 ethyl 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2-carboxylateIntermediate 17

Step 1: 2-nitro-N-(prop-2-ynyl)benzenesulfonamide Intermediate 14

A solution of propargylamine (2 mL, 29 mmol) andN,N-diisopropylethylamine (10 mL, 57.4 mmol) in methylene chloride (100mL) was cooled to 0° C. 2-nitrobenzenesulfonyl chloride (6.46 g, 29.2mmol) was added portionwise. Upon complete addition, the solution wasallowed to warm to room temperature and was further stirred at roomtemperature overnight. The reaction solution was concentrated in vacuoand the residue obtained was directly purified on silica chromatography(20-50% EtOAc/hexane) to afford Intermediate 14 as white solid (5.90 g,84%). LC-MS: (FA) ES+241; ¹H NMR (400 MHz, CDCl₃) δ 8.22-8.17 (m, 1H),7.94-7.89 (m, 1H), 7.79-7.73 (m, 2H), 5.71 (s, 1H), 4.02 (dd, J=5.9, 2.4Hz, 2H), 1.97 (t, J=2.5 Hz, 1H).

Step 2: N-(2-chloroethyl)-2-nitro-N-(prop-2-ynyl)benzenesulfonamideIntermediate 15

To a mixture of 2-nitro-N-(prop-2-yn-1-yl)benzenesulfonamide (0.448 g,1.86 mmol) and cesium carbonate (1.75 g, 5.37 mmol) in acetone (10 mL)was added neat 1-bromo-2-chloroethane (0.775 mL, 9.31 mmol) dropwise.The reaction mixture was stirred at room temperature for 20 hours. Thereaction mixture was concentrated and the residue partitioned betweenEtOAc (25 mL) and water (15 mL). The aqueous layer was extracted withadditional EtOAc (20 mL), the combined organic layers dried overanhydrous MgSO4 and concentrated. Purification via silica chromatography(25-40% EtOAc/hexane) afforded an oil (0.540 g, 96%). LC-MS: (FA)ES+303. ¹H NMR (400 MHz, CDCl₃) δ 8.08 (dt, J=8.2, 3.7 Hz, 1H),7.77-7.64 (m, 3H), 4.30 (d, J=2.5 Hz, 2H), 3.78-3.68 (m, 4H), 2.23 (t,J=2.5 Hz, 1H).

Step 3: ethyl5-(2-nitrophenylsulfonyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2-carboxylateIntermediate 16

A solution ofN-(2-chloroethyl)-2-nitro-N-(prop-2-yn-1-yl)benzenesulfonamide (0.51 g,1.69 mmol and ethyl diazoacetate (0.266 mL, 2.532 mmol) in benzene (2mL) was heated in a microwave reactor at 140° C. for 1 hour. Uponcooling to room temperature, cesium carbonate (0.637 g, 1.95 mmol) alongwith tetrahydrofuran (1 mL) was added. The vial was again sealed andheated at 140° C. for 30 minutes in the microwave reactor. Upon coolingto room temperature, the solvents were then evaporated in vacuo and theresidue obtained was partitioned between water (10 mL) and EtOAc (15mL). The aqueous layer was washed with additional EtOAc (15 mL), thecombined organic layers were dried over anhydrous MgSO4, concentratedand purified via silica chromatography (20-90% EtOAc/hexane) to affordIntermediate 16 as a semi solid (0.235 g, 37%). LC-MS: (FA) ES+381; ¹HNMR (400 MHz, CDCl₃) δ 8.07 (dd, J=7.5, 1.7 Hz, 1H), 7.79-7.67 (m, 3H),6.63 (s, 1H), 4.64 (s, 2H), 4.41-4.31 (m, 4H), 3.92-3.89 (m, 2H), 1.37(t, J=7.1 Hz, 3H).

Step 4: ethyl 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2-carboxylateIntermediate 17

To a mixture of ethyl5-[(2-nitrophenyl)sulfonyl]-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2-carboxylate(0.216 g, 0.568 mmol) and cesium carbonate (0.35 g, 1.1 mmol) was addeda solution of benzenethiol (0.11 mL, 1.1 mmol) in acetonitrile (1 mL).The resulting reaction mixture was stirred at room temperature for 1hour. The solvent was removed in vacuo and the residue applied directlyto silica purification (5% MeOH/DCM with 1% Et₃N) to afford Intermediate17 as a white solid (0.093 g, 84%). LC-MS: (FA) ES+196; ¹H NMR (400 MHz,CDCl₃) δ 6.49 (s, 1H), 4.35 (q, J=7.1 Hz, 2H), 4.17-4.13 (m, 2H), 4.04(s, 2H), 3.29-3.25 (m, 2H), 1.74 (s, 1H), 1.35 (t, J=7.1 Hz, 3H).

Example 12N-(tetrahydro-2H-pyran-2-yloxy)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxamideIntermediate 22

Step 1: N-(3-chloropropyl)-2-nitro-N-(prop-2-ynyl)benzenesulfonamideIntermediate 18

To a mixture of 2-nitro-N-(prop-2-yn-1-yl)benzenesulfonamide (1.08 g,4.48 mmol) and cesium carbonate (7.30 g, 22.42 mmol) in acetone (40 mL)was added neat 1-bromo-3-chloropropane (6.5 mL, 66 mmol) dropwise. Uponcomplete addition, the reaction mixture was stirred at room temperaturefor 2 days. The reaction mixture was concentrated and the residuepartitioned between EtOAc (25 mL) and water (15 mL). The aqueous layerwas extracted with additional EtOAc (20 mL), the combined organic layersdried over anhydrous MgSO₄ and concentrated. Purification via silicachromatography (25-40% EtOAc/hexane) afforded Intermediate 18 as an oil(0.9764 g, 69%). ¹H NMR (400 MHz, CDCl₃) δ 8.10-8.05 (m, 1H), 7.76-7.62(m, 3H), 4.22 (d, J=2.5 Hz, 2H), 3.57 (td, J=6.6, 2.9 Hz, 4H), 2.21 (t,J=2.5 Hz, 1H), 2.14-2.06 (m, 2H).

Step 2: ethyl5-(2-nitrophenylsulfonyl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxylateIntermediate 19

To a solution ofN-(3-chloropropyl)-2-nitro-N-(prop-2-yn-1-yl)benzenesulfonamide (0.5 g,1.59 mmol) and ethyl diazoacetate (0.251 mL, 2.384 mmol) in benzene (1.5mL) was added N,N-diisopropylethylamine (0.27 mL, 1.6 mmol). Theresulting solution was heated in a microwave reactor at 140° C. for 1hour. Upon cooling to room temperature, cesium carbonate (0.621 g, 1.91mmol) and tetrahydrofuran (1 mL) was added and the reaction mixtureagain heated at 140° C. for 30 minutes. Upon cooling to roomtemperature, the solvents were evaporated and the residue obtained waspartitioned between water (10 mL) and EtOAc (15 mL). The aqueous layerwas washed with additional EtOAc (15 mL), the combined organic layerswere dried over anhydrous MgSO₄, concentrated and purified via silicachromatography (20-90% EtOAc/hexane) to afford Intermediate 19 as ayellow oil (0.314 g, 50%). LC-MS: (FA) ES+395; ¹H NMR (400 MHz, CDCl₃) δ7.96 (dd, J=7.8, 1.5 Hz, 1H), 7.73-7.60 (m, 3H), 6.77 (s, 1H), 4.58 (s,2H), 4.52-4.47 (m, 2H), 4.37 (q, J=7.1 Hz, 2H), 3.72-3.65 (m, 2H),2.10-2.04 (m, 2H), 1.37 (t, J=7.1 Hz, 3H).

Step 3:5-(2-nitrophenylsulfonyl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxylicacid Intermediate 20

Ethyl5-[(2-nitrophenyl)sulfonyl]-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxylate(0.143 g, 0.362 mmol) was dissolved in a mixture of THF (4 mL) andmethanol (1 mL) and to the solution was added 1.0 M of lithium hydroxidein water (1.5 mL, 1.5 mmol). The resulting mixture was stirred at roomtemperature for 2 hours. The mixture was concentrated, and the residuewas dissolved in water (5 mL) and neutralized with 1.0 M hydrochloricacid in water (1.5 mL, 1.5 mmol). The resulting precipitate wascollected via vacuum filtration to afford Intermediate 20 as a whitesolid (0.1166 g, 88%). LC-MS: (FA) ES+395.

Step 4:5-(2-nitrophenylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxamideIntermediate 21

To a solution of5-[(2-nitrophenyl)sulfonyl]-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxylicacid (0.116 g, 0.316 mmol) and O-(tetrahydropyran-2-yl)hydroxylamine(0.0407 g, 0.347 mmol) in methylene chloride (2.5 mL) was addedN,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uroniumhexafluorophosphate (0.144 g, 0.379 mmol) and N-methylmorpholine (0.1mL, 0.9 mmol). The resulting reaction mixture was stirred at roomtemperature overnight. The solvent was evaporated and the residueobtained purified via silica chromatography (80-100% EtOAc/hexane) toafford Intermediate 21 as a clear colorless oil (0.152 g, 100%). LC-MS:(FA) ES+466.

Step 5:N-(tetrahydro-2H-pyran-2-yloxy)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxamideIntermediate 22

To a mixture of5-[(2-nitrophenyl)sulfonyl]-N-(tetrahydro-2H-pyran-2-yloxy)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxamide(0.15 g, 0.32 mmol) and cesium carbonate (0.2 g, 0.62 mmol) inacetonitrile (10 mL) was added a solution of benzenethiol (0.063 mL,0.62 mmol) in acetonitrile (0.60 mL). The resulting reaction mixture wasstirred at room temperature for 1 hour. The solvent was evaporated andthe residue applied directly to silica purification (5% MeOH/DCM) toafford the title compound as a white solid (0.082 g, 91%). LC-MS: (FA)ES+281; ¹H NMR (400 MHz, CDCl₃) δ 6.59 (s, 1H), 5.30 (s, 1H), 5.08 (s,1H), 4.39-4.32 (m, 2H), 4.08-4.00 (m, 1H), 3.92 (q, J=15.7 Hz, 2H),3.71-3.61 (m, 1H), 3.26-3.15 (m, 2H), 2.29 (s, 1H), 1.92-1.79 (m, 5H),1.70-1.54 (m, 3H).

Example 13N-hydroxy-5-(3-methylbenzo[b]thiophene-2-carbonyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2-carboxamideCompound I-97

Step 1: ethyl5-(3-methylbenzo[b]thiophene-2-carbonyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2-carboxylateIntermediate 23

To a mixture of ethyl4,5,6,7-tetrandropyrazolo[1,5-a]pyrazine-2-carboxylate (0.029 g, 0.15mmol) and 3-methylbenzo[b]thiophene-2-carboxylic acid (0.0314 g, 0.163mmol) in methylene chloride (1.5 mL) was addedN,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uroniumhexafluorophosphate (0.0678 g, 0.178 mmol) and N-methylmorpholine (0.05mL, 0.446 mmol). The reaction mixture was stirred at room temperatureovernight. The reaction was diluted with additional methylene chloride(1.5 mL) and was washed with aqueous NaHCO₃ (2 mL). The layers wereseparated and the aqueous layer was extracted with additional methylenechloride (3 mL) and the combined organic layers evaporated to dryness togive crude ethyl5-(3-methylbenzo[b]thiophene-2-carbonyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2-carboxylateIntermediate 23.

Step 2:5-(3-methylbenzo[b]thiophene-2-carbonyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2-carboxylicacid Intermediate 24

The ethyl5-(3-methylbenzo[b]thiophene-2-carbonyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2-carboxylateobtained in the previous step was dissolved in a mixture oftetrahydrofuran (1.8 mL) and methanol (0.3 mL). To the resultingsolution was added 1M aqueous sodium hydroxide (0.4 mL, 0.4 mmol). Thesolution was stirred at room temperature for 4 hours whereupon thereaction was neutralized with the addition of 1M aqueous hydrochloricacid (0.4 mL). The solvents were evaporated under reduced pressure toafford crude Intermediate 24 as a white solid.

Step 3:5-(3-methylbenzo[b]thiophene-2-carbonyl)-N-(tetrahydro-2H-pyran-2-yloxy)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2-carboxamideIntermediate 25

To a mixture of5-(3-methylbenzo[b]thiophene-2-carbonyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2-carboxylicacid obtained in the previous step and0-(tetrahydropyran-2-yl)hydroxylamine (0.035 g, 0.3 mmol) in methylenechloride (1.5 mL) was addedN,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uroniumhexafluorophosphate (0.085 g, 0.22 mmol) and N-methylmorpholine (0.05mL, 0.44 mmol). The resulting mixture was stirred overnight at roomtemperature. The reaction was then diluted with additional methylenechloride (1.5 mL) and washed with aqueous NaHCO₃ (2 mL). The separatedaqueous layer was extracted with methylene chloride (3 mL) and thecombined organic layers were concentrated to afford crude Intermediate25.

Step 4:N-hydroxy-5-(3-methylbenzo[b]thiophene-2-carbonyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2-carboxamideCompound I-97

The crude intermediate 25 obtained in the previous step was taken up intetrahydrofuran (1 mL) and to the solution was added 4M hydrochloricacid in 1,4-dioxane (0.50 mL, 2 mmol). The reaction was stirred at roomtemperature for 1.5 hours. The solution was evaporated to dryness, theresidue dissolved in DMSO (1 mL) and purified on Gilson prep-HPLC toafford the title compound as a white solid (0.0043 g, 8%). LC-MS: (FA)ES+357; ¹H NMR (400 MHz, DMSO) δ 10.95 (s, 1H), 8.91 (s, 1H), 8.05-7.95(m, 1H), 7.90-7.82 (m, 1H), 7.51-7.45 (m, 2H), 6.49 (s, 1H), 4.84 (s,2H), 4.21 (s, 2H), 4.04 (s, 2H), 2.38 (s, 3H).

Example 14

The following compounds were prepared in an analogous fashion to thatdescribed in Example 13 starting from the intermediates which wereprepared as described above and the corresponding carboxylic acids.

LC-MS Compound (FA) I-6 ES+ 307 I-97 ES+ 357 I-36 ES+ 267

Example 15N-hydroxy-5-(1H-indol-3-ylacetyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2-carboxamideCompound I-102

Step 1: ethyl5-(2-(1H-indol-3-yl)acetyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2-carboxylateIntermediate 26

To a mixture of ethyl4,5,6,7-tetrandropyrazolo[1,5-a]pyrazine-2-carboxylate (0.02 g, 0.1mmol) and indole-3-acetic acid (0.019 g, 0.11 mmol) in methylenechloride (1.5 mL) was addedN,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uroniumhexafluorophosphate (0.046 g, 0.12 mmol) and N-methylmorpholine (0.02mL, 0.2 mmol). The reaction mixture was stirred at room temperatureovernight. The reaction was diluted with additional methylene chloride(1.5 mL) and washed with aqueous NaHCO₃ (2 mL). The layers wereseparated and the aqueous layer was extracted with additional methylenechloride (3 mL) and the combined organic layers evaporated to dryness togive crude ethyl5-(2-(1H-indol-3-yl)acetyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2-carboxylate.

Step 2:N-hydroxy-5-(1H-indol-3-ylacetyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2-carboxamideCompound I-102

To a solution of ethyl5-(2-(1H-indol-3-yl)acetyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2-carboxylateobtained in the previous step in methanol (0.5 mL) was added 1.7 Mhydroxylamine potassium salt in methanol (0.5 mL, 0.85 mmol; prepared asdescribed in Journal of Medicinal Chemistry 2009, 52(21):6757). Thereaction mixture was stirred at room temperature for 1 hour. Uponevaporation of the solvent, the resulting residue was dissolved in DMSO(1 mL) and purified using an Agilent 1100 LC/MSD instrument to affordthe title compound as a white solid (11.0 mg, 32%). LC-MS: (FA) ES+340.

Example 16

The following compounds were prepared in an analogous fashion to thatdescribed in Example 15 starting from the intermediates which wereprepared as described above and the corresponding carboxylic acids.

LC-MS Compound (FA) I-90 ES+ 322 I-106 ES+ 315 I-107 ES+ 338 I-11 ES+358 I-37 ES+ 363 I-31 ES+ 340 I-8 ES+ 319 I-17 ES+ 393 I-93 ES+ 354

Example 17N-hydroxy-5-(4-methoxybenzoyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2-carboxamideCompound I-100

Step 1: ethyl5-(4-methoxybenzoyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2-carboxylateIntermediate 27

To a solution of 4-methoxybenzoic acid (0.187 g, 1.23 mmol) dissolved inN,N-dimethylformamide (5 mL) and triethylamine (0.428 mL, 3.07 mmol) wasadded tetramethylfluoroformamidinium hexafluorophosphate (0.406 g, 1.54mmol) and the reaction mixture was stirred for 15 minutes. Ethyl4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2-carboxylate (0.2 g, 1.02mmol) was added and the reaction continued to stir at room temperaturefor 5 hours. The reaction mixture was diluted with water and extractedwith EtOAc (3×). The combined organic layers were washed with water,brine, dried over anhydrous Na₂SO₄, filtered and concentrated. Theresidue was purified via silica gel chromatography (0-90% EtOAc/hexane)to afford ethyl5-(4-methoxybenzoyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2-carboxylateIntermediate 27 (0.359 g, 100%). LC-MS: (FA) ES+330.

Step 2:5-(4-methoxybenzoyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2-carboxylicacid Intermediate 28

To a solution of ethyl5-(4-methoxybenzoyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2-carboxylate(0.359 g, 1.09 mmol) obtained in the previous step dissolved intetrahydrofuran (5 mL), ethanol (5 mL) and water (3 mL) was addedlithium hydroxide (0.039 g, 1.64 mmol) and the reaction was stirred atroom temperature for 2 hours. The solvent was then concentrated and theremaining aqueous solution was acidified with 1M aqueous hydrochloricacid to pH=1 resulting in the formation of a solid precipitate. EtOAcwas added to dissolve the precipitate and the organic layer wasseparated and the aqueous layer was re-extracted with EtOAc (2×). Thecombined organic layers were then washed with water, brine, dried overNa₂SO₄, filtered and concentrated to afford5-(4-methoxybenzoyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2-carboxylicacid Intermediate 28 (0.205 g, 62%). LC-MS: (FA) ES+302.

Step 3:5-(4-methoxybenzoyl)-N-(tetrahydro-2H-pyran-2-yloxy)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2-carboxamideIntermediate 29

To a solution of5-(4-methoxybenzoyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2-carboxylicacid obtained in the previous step (0.205 g, 0.68 mmol) dissolved inN,N-dimethylformamide (5 mL) and triethylamine (0.284 mL, 2.04 mmol) wasadded tetramethylfluoroformamidinium hexafluorophosphate (0.216 g, 0.816mmol) and the reaction mixture was stirred for 15 minutes. SolidO-(tetrahydropyran-2-yl)hydroxylamine (0.096 g, 0.816 mmol) was addedand the reaction continued to stir at room temperature for 4 hours. Thereaction mixture was then diluted with water and extracted with EtOAc(3×). The combined organic layers were then washed with water, brine,dried using anhydrous Na₂SO₄, filtered and concentrated. The residue waspurified via silica gel chromatography (0-10% MeOH/DCM) to afford5-(4-methoxybenzoyl)-N-(tetrahydro-2H-pyran-2-yloxy)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2-carboxamide(0.167 g, 61%). LC-MS: (FA) ES+401.

Step 4:N-hydroxy-5-(4-methoxybenzoyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2-carboxamideCompound I-100

To a solution of5-(4-methoxybenzoyl)-N-(tetrahydro-2H-pyran-2-yloxy)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2-carboxamide(0.167 g, 0.417 mmol) obtained in the previous step dissolved inmethanol (4 mL) was added 4.0 M of hydrochloric acid in 1,4-dioxane(0.021 mL, 0.083 mmol) and the reaction was stirred at room temperaturefor 3 hours. The solvent was then concentrated to dryness and theresidue was purified on a BioCAD 700E HPLC instrument using a Phenomenex(C18) Luna (21.2 mm×250 mm) column to affordN-hydroxy-5-(4-methoxybenzoyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2-carboxamide(0.018 g, 14%). LC-MS: (AA) ES+317.

Example 18

The following compound was prepared in an analogous fashion to thatdescribed in Example 17 starting from the intermediates which wereprepared as described above and the corresponding carboxylic acid.

LC-MS Compound (AA) I-76 ES+ 290

Example 19N-hydroxy-5-(4-methoxybenzoyl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxamideCompound I-53

Step 1:5-(4-methoxybenzoyl)-N-(tetrahydro-2H-pyran-2-yloxy)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxamideIntermediate 30

To a mixture ofN-(tetrahydro-2H-pyran-2-yloxy)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxamide(0.0283 g, 0.101 mmol) and 4-methoxybenzoic acid (0.016 g, 0.105 mmol)in methylene chloride (1 mL) was addedN,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uroniumhexafluorophosphate (0.0434 g, 0.114 mmol) and N-methylmorpholine(0.0333 mL, 0.303 mmol). The reaction mixture was stirred at roomtemperature overnight. The reaction mixture was diluted with methylenechloride (2 mL) and washed with aqueous NaHCO₃ (2 mL). The aqueous layerwas extracted with additional methylene chloride (3 mL) and the combinedorganic layers concentrated to afford Intermediate 30 as a white solid.

Step 2:N-hydroxy-5-(4-methoxybenzoyl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxamideCompound I-53

The material obtained in the previous step was taken up intetrahydrofuran (1 mL) and to the resulting solution was added 4 M ofhydrochloric acid in 1,4-dioxane (0.2 mL, 0.8 mmol). The reaction wasstirred at room temperature for 1 hour, then evaporated to dryness, andthe residue obtained was dissolved in DMSO (1 mL) and purified on Gilsonprep-HPLC to afford the title compound as a white powder (19.3 mg, 58%over two steps). LC-MS: (FA) ES+331; ¹H NMR (400 MHz, DMSO) δ 10.87 (s,1H), 8.92 (s, 1H), 7.29 (d, J=7.9 Hz, 2H), 6.97 (d, J=8.4 Hz, 2H), 4.72(s, 2H), 4.46-4.42 (m, 2H), 3.79 (s, 3H), 3.33 (s, 2H), 1.87 (s, 2H).

Example 20N-hydroxy-5-[(5-pyridin-2-yl-2-thienyl)carbonyl]-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxamideCompound I-70

Step 1: ethyl5-(5-(pyridin-2-yl)thiophene-2-carbonyl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxylateIntermediate 31

To a mixture of ethyl5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxylate (0.033g, 0.16 mmol) and 5-(2-pyridyl)thiophene-2-carboxylic acid (0.036 g,0.18 mmol) in methylene chloride (1 mL) was addedN,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uroniumhexafluorophosphate (0.07 g, 0.184 mmol) and N-methylmorpholine (0.053mL, 0.48 mmol). The reaction was stirred overnight at room temperature.The reaction was diluted with methylene chloride (3 mL) and washed withsaturated aqueous NaHCO₃ (2 mL). The aqueous layer was extracted withadditional methylene chloride (3 mL). The combined organic layers weredried over anhydrous Na₂SO₄, filtered and concentrated to dryness toafford Intermediate 31.

Step 2:N-hydroxy-5-(5-(pyridin-2-yl)thiophene-2-carbonyl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxamideCompound I-70

A mixture of hydroxylamine hydrochloride (2.35 g, 33.8 mmol) and lithiumhydroxide (1.43 g, 59.7 mmol) in anhydrous methanol (20 mL) was heatedat 90° C. for 1 hour in a sealed 50 mL pressure flask. Upon cooling toroom temperature 1 mL of the filtered solution was added to the materialprepared in the previous step dissolved in methanol (0.5 mL). Theresulting reaction solution was stirred at room temperature for 1 hour.Upon quenching with the addition of formic acid (0.1 mL, 2.6 mmol), thesolvent was evaporated to dryness and the residue obtained was dissolvedin DMSO (1 mL) and purified on an Agilent 1100 LC/MSD instrument toafford the title compound as a white solid (19.1 mg, 31%). LC-MS: (FA)ES+384; ¹H NMR (400 MHz, DMSO) δ 10.89 (s, 1H), 8.88 (s, 11-1), 8.55(ddd, J=4.9, 1.7, 0.9 Hz, 1H), 7.99 (d, J=8.0 Hz, 1H), 7.87 (td, J=7.8,1.8 Hz, 1H), 7.79 (d, J=3.9 Hz, 1H), 7.43 (d, J=3.9 Hz, 1H), 7.33 (ddd,J=7.5, 4.9, 1.0 Hz, 1H), 6.54 (s, 1H), 4.84 (s, 2H), 4.52-4.43 (m, 2H),3.99 (s, 2H), 2.00 (s, 2H).

Example 21

The following compounds were prepared in an analogous fashion to thatdescribed in Example 20 starting from the intermediates which wereprepared as described above and the corresponding carboxylic acids.

LC-MS Compound (FA) I-108 ES+ 355 I-72 ES+ 359 I-105 ES+ 354 I-98 ES+357

Example 225-benzyl-N-hydroxy-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2-carboxamideCompound I-81

Step 1: ethyl5-benzyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2-carboxylateIntermediate 32

To a solution of ethyl4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2-carboxylate (30 mg,0.143 mmol) in acetonitrile (1 mL) was added cesium carbonate (93.4 mg,0.287 mmol) and benzyl bromide (25.6 μL, 0.215 mmol). The reactionmixture was stirred overnight at 70° C. Upon cooling to roomtemperature, the cesium carbonate was removed by filtration and thesolvent evaporated under reduced pressure to afford crude Intermediate32. LC-MS: (AA) ES+300.

Step 2:5-benzyl-N-hydroxy-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2-carboxamideCompound I-81

To a solution of the material obtained in the previous step in methanol(3 mL) was added solid potassium hydroxide (100 mg, 2 mmol) andhydroxylamine hydrochloride (50 mg, 0.72 mmol). The reaction mixture washeated at 80° C. for 30 minutes. Upon cooling to room temperature allsolids were removed via filtration and the solvent evaporated todryness. The residue was dissolved in DMSO (1 mL) and purified on anAgilent 1100 LC/MSD instrument to afford the title compound as a whitesolid (9.1 mg, 21%). ¹H NMR (400 MHz, MeOD) δ 7.39-7.26 (m, 5H), 7.23(s, 1H), 4.76 (s, 2H), 4.42-4.38 (m, 2H), 3.77 (dd, J=6.9, 5.5 Hz, 2H);LC-MS: (AA) ES+287.

Example 235-(cyclopropylmethyl)-N-hydroxy-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2-carboxamideCompound I-83

Step 1: ethyl5-(cyclopropylmethyl)-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2-carboxylateIntermediate 33

To a solution of cyclopropylmethyl bromide (0.101 g, 0.75 mmol) andethyl 4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2-carboxylate(31.4 mg, 0.150 mmol) in acetonitrile (2 mL) was added cesium carbonate(147 mg, 0.45 mmol). The reaction mixture was heated overnight at 70° C.Upon cooling to room temperature, the insolubles were removed byfiltration and the solvent evaporated to dryness to afford crudeIntermediate 33.

Step 2:5-(cyclopropylmethyl)-N-hydroxy-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2-carboxamideCompound I-83

To a solution of the material obtained in the previous step in methanol(1 mL) was added 1.7 M hydroxylamine potassium salt in methanol (1 mL,1.7 mmol; prepared as described in Journal of Medicinal Chemistry 2009,52(21):6757). The reaction mixture was stirred at room temperature for 1hour. Upon evaporation of the solvent the residue was dissolved in DMSO(1 mL) and purified on a Agilent 1100 LC/MSD instrument to afford thetitle compound as a white solid (8.4 mg, 22%). LC-MS: (FA) ES+251.

Example 24

The following compounds were prepared in an analogous fashion to thatdescribed in Example 23 starting from the intermediates which wereprepared as described above and the corresponding starting materials.

Compound LC-MS (FA) I-103 ES+ 355 I-24 ES+ 293 I-77 ES+ 367 I-12 ES+ 305I-88 ES+ 269 I-50 ES+ 281 I-110 ES+ 321 I-65 ES+ 315 I-48 ES+ 317 I-46ES+ 239 I-67 ES+ 343 I-109 ES+ 304

Example 252-benzyl-N-hydroxy-1-oxo-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-7-carboxamideCompound I-42

Step 1: ethyl2-benzyl-1-oxo-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-7-carboxylateIntermediate

To a solution of ethyl1-oxo-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-7-carboxylate (29.8 mg,0.143 mmol) in acetonitrile (1 mL) was added cesium carbonate (60.6 mg,0.186 mmol) and benzyl bromide (36.7 mg, 0.215 mmol). The reactionmixture was heated at 70° C. overnight. Upon cooling to room temperatureall insolubles were removed by filtration and the solvent evaporated todryness to afforde crude Intermediate 34.

Step 2:2-benzyl-N-hydroxy-1-oxo-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-7-carboxamideCompound I-42

A mixture of potassium hydroxide (100 mg, 2 mmol) and hydroxylaminehydrochloride (49.7 mg, 0.715 mmol) in dimethyl sulfoxide (1 mL) wassonicated until the hydroxylamine hydrochloride had gone into solution.After removal of insolubles, the solution was added to Intermediate 34obtained in the previous step and the solution stirred at roomtemperature overnight. The solution was purified directly on an Agilent1100 LC/MSD instrument to afford the title compound as a white solid(4.9 mg, 12%). ¹H NMR (400 MHz, MeOD) δ 7.42-7.24 (m, 6H), 7.15 (s, 1H),4.74 (s, 2H), 4.18 (dd, J=12.2, 6.1 Hz, 2H), 3.64 (dd, J=6.7, 5.1 Hz,2H). LC-MS: (FA) ES+286.

Example 26

The following compound was prepared in an analogous fashion to thatdescribed in Example 25 starting from the intermediates which wereprepared as described above and the corresponding starting material.

LC-MS Compound (FA) I-49 ES+ 300 I-197 ES+ 367 I-240 ES− 352 I-241 ES+250

Example 27N-hydroxy-7-(1-methylcyclohexanecarbonyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-2-carboxamideCompound I-26

Step 1: ethyl7-(1-methylcyclohexanecarbonyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-2-carboxylateIntermediate 35

To a vial was added 1-methyl-1-cyclohexanecarboxylic acid (0.024 g,0.168 mmol), HATU (0.064 g, 0.168 mmol), triethylamine (0.134 mL, 0.96mmol), DCM (2 mL), and DMF (0.2 mL). After shaking for 30 min, ethyl5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-2-carboxylate (0.031 g, 0.16mmol) was added. The mixture was shaken at rt for 16 h. To the vial wasadded water (1 mL) and DCE (1 mL). After separation, the aqueous layerwas extracted with DCE twice (3 mL). The combined organic layers wereconcentrated to give crude ethyl7-(1-methylcyclohexanecarbonyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-2-carboxylateas a solid.

Step 2: ethyl7-(1-methylcyclohexanecarbonyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-2-carboxylateCompound I-26

Preparation of NH₂OK solution (1.76 M in methanol): A suspension ofhydroxylamine hydrochloride (9.4 g, 135 mmol) in methanol (48 mL) washeated at 68° C. under argon until a clear solution was obtained. Tothis solution was added a solution of potassium hydroxide (13.4 g, 239mmol) in methanol (28 mL). After refluxing at 80° C. for 30 min, themixture was cooled to room temperature and the upper clear solution(approximately 1.76 M NH₂OH in methanol) was used directly in furtherreactions.

To the crude ethyl7-(1-methylcyclohexanecarbonyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-2-carboxylatein a vial was added methanol (1 mL), and NH₂OK solution (1 mL, 1.76 M inmethanol). The mixture was stirred at rt for 1 h. To the reaction wasadded acetic acid (0.182 mL, 3.2 mmol). After stirring for 5 min, thesolvent was completely evaporated. The residue was dissolved in DMSO(1.2 mL), filtered, and purified by prep-HPLC to give ethyl7-(1-methylcyclohexanecarbonyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-2-carboxylate(0.01 g, 32.6%) as a white solid. LC-MS (FA): ES+307; ¹H NMR(Methanol-d₄, 400 MHz) δ7.58 (s, 1H), 4.82 (s, 2H), 4.10 (m, 4H), 2.06(m, 2H), 1.60-1.35 (m, 8H), 1.27 (s, 3H).

Example 28

The following compounds were prepared in an analogous fashion to thatdescribed in Example 27 using the corresponding starting materials.

Compound LC-MS No (FA) I-44 ES+ 343 I-41 ES+ 267 I-13 ES+ 317 I-14 ES+290 I-60 ES+ 377 I-57 ES+ 321 I-21 ES+ 327 I-2 ES+ 363 I-27 ES+ 345 I-45ES+ 343 I-55 ES+ 308 I-101 ES+ 385

Example 29N-2-hydroxy-N-7-o-tolyl-5,6-dihydroimidazo[1,2-a]pyrazine-2,7(8H)dicarboxamide Compound I-117

Step 1: ethyl7-(o-tolylcarbamoyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-2-carboxylateIntermediate 36

To a vial containing 1-isocyanato-2-methylbenzene (0.0166 g, 0.125 mmol)was added ethyl 5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-2-carboxylate(0.024 g, 0.125 mmol), DIPEA (0.0762 mL, 0.438 mmol), and DMF (1.5 mL).The solution was shaken at room temperature for 16 h, then concentratedto give crude ethyl7-(o-tolylcarbamoyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-2-carboxylate.

Step 2:N-2-hydroxy-N-7-o-tolyl-5,6-dihydroimidazo[1,2-a]pyrazine-2,7(8H)dicarboxamide Compound I-117

The NH₂OK solution was prepared as described above in Example 27. Tocrude ethyl7-(o-tolylcarbamoyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-2-carboxylatefrom step 1 was added methanol (1 mL) and NH₂OK solution (1 mL, 1.76 Min MeOH). The solution was stirred at room temperature for 1 hour.Acetic acid (0.2 mL, 2.8 mmol) was added to neutralize the excess base.The solution was then concentrated, taken-up in DMSO (1.2 mL), filtered,and purified by prep-HPLC to give N-2-hydroxy-N-7-o-tolyl-5,6dihydroimidazo[1,2-a]pyrazine-2,7(8H) dicarboxamide (0.096 g, 24.3%) asa white solid. LC-MS (FA): ES+316; ¹H NMR (Methanol-d₄, 400 MHz) δ7.62(s, 1H), 7.24-7.12 (m, 4H), 4.78 (s, 2 H), 4.20 (t, J=4.8 Hz, 2H), 3.99(t, J=5.8 Hz, 2H), 2.22 (s, 3H).

Example 30

The following compounds were prepared in an analogous fashion to thatdescribed in Example 29 using the corresponding starting materials.

LC-MS Compound (FA) I-118 ES+ 282 I-122 ES+ 383 I-123 ES+ 316 I-113 ES+360 I-116 ES+ 302 I-115 ES+ 358 I-112 ES+ 358 I-120 ES+ 330 I-114 ES+378 I-119 ES+ 282 I-121 ES+ 308

II. BIOLOGICAL DATA Example 31 HDAC6 enzyme assay

To measure the inhibition of HDAC6 activity, purified human HDAC6 (BPSBioscience; Cat. No. 5006) is incubated with substrateAc-Arg-Gly-Lys(Ac)-AMC peptide (Bachem Biosciences; Cat. No. I-1925) for1 hour at 30° C. in the presence of test compounds or vehicle DMSOcontrol. The reaction is stopped with the HDAC inhibitor trichostatin A(Sigma; Cat. No. T8552) and the amount of Arg-Gly-Lys-AMC generated isquantitated by digestion with trypsin (Sigma; Cat. No. T1426) andsubsequent measurement of the amount of AMC released using a fluorescentplate reader (Pherastar; BMG Technologies) set at Ex 340 nm and Em 460nm. Concentration response curves are generated by calculating thefluorescence increase in test compound-treated samples relative toDMSO-treated controls, and enzyme inhibition (IC₅₀) values aredetermined from those curves.

Example 32 Nuclear extract HDAC assay

As a screen against Class I HDAC enzymes, HeLa nuclear extract (BIOMOL;Cat. No. KI-140) is incubated with Ac-Arg-Gly-Lys(Ac)-AMC peptide(Bachem Biosciences; Cat. No. 1-1925) in the presence of test compoundsor vehicle DMSO control. The HeLa nuclear extract is enriched for ClassI enzymes HDAC1, -2 and -3. The reaction is stopped with the HDACinhibitor Trichostatin A (Sigma; Cat. No. T8552) and the amount ofArg-Gly-Lys-AMC generated is quantitated by digestion with trypsin(Sigma; Cat. No. T1426) and subsequent measurement of the amount of AMCreleased using a fluorescent plate reader (Pherastar; BMG Technologies)set at Ex 340 nm and Em 460 nm. Concentration response curves aregenerated by calculating the fluorescence increase in testcompound-treated samples relative to DMSO-treated controls, and enzymeinhibition (IC₅₀) values are determined from those curves.

Example 33 Western Blot and Immunofluorescence Assays

Cellular potency and selectivity of compounds are determined using apublished assay (Haggarty et al., Proc. Natl. Acad. Sci. USA 2003, 100(8): 4389-4394) using Hela cells (ATCC cat#CCL-2™) which are maintainedin MEM medium (Invitrogen) supplemented with 10% FBS; or multiplemyeloma cells RPMI-8226 (ATCC cat#CCL-155™) which are maintained in RPMI1640 medium (Invitrogen) supplemented with 10% FBS. Briefly, cells aretreated with inhibitors for 6 or 24 h and either lysed for Westernblotting, or fixed for immunofluorescence analyses. HDAC6 potency isdetermined by measuring K40 hyperacetylation of alpha-tubulin with anacetylation selective monoclonal antibody (Sigma cat#T7451) in IC50experiments. Selectivity against Class I HDAC activity is determinedsimilarly using an antibody that recognizes hyperacetylation of histoneH4 (Upstate cat#06-866) in the Western blotting assay or nuclearacetylation (Abeam cat#ab21623) in the immunofluorescence assay.

Example 34 In vivo Tumor Efficacy Model

Female NCr-Nude mice (age 6-8 weeks, Charles River Labs) are asepticallyinjected into the subcutaneous space in the right dorsal flank with1.0−5.0×10⁶ cells (SKOV-3, HCT-116, BxPC3) in 100 μL of a 1:1 ratio ofserum-free culture media (Sigma Aldrich) and BD Matrigel™ (BDBiosciences) using a 1 mL 26⅜ gauge needle (Becton DickinsonRef#309625). Alternatively, some xenograft models require the use ofmore immunocompromised strains of mice such as CB-17 SCID (Charles RiverLabs) or NOD-SCID (Jackson Laboratory). Furthermore, some xenograftmodels require serial passaging of tumor fragments in which smallfragments of tumor tissue (approximately 1 mm³) are implantedsubcutaneously in the right dorsal flank of anesthetized (3-5%isoflourane/oxygen mixture) NCr-Nude, CB-17 SCID or NOD-SCID mice (age5-8 weeks, Charles River Labs or Jackson Laboratory) via a 13-ga trocarneedle (Popper & Sons 7927). Tumor volume is monitored twice weekly withVernier calipers. The mean tumor volume is calculated using the formulaV=W²×L/2. When the mean tumor volume is approximately 200 mm³, theanimals are randomized into treatment groups of ten animals each. Drugtreatment typically includes the test compound as a single agent, andmay include combinations of the test compound and other anticanceragents. Dosing and schedules are determined for each experiment based onprevious results obtained from pharmacokinetic/pharmacodynamic andmaximum tolerated dose studies. The control group will receive vehiclewithout any drug. Typically, test compound (100-200 μL) is administeredvia intravenous (27-ga needle), oral (20-ga gavage needle) orsubcutaneous (27-ga needle) routes at various doses and schedules. Tumorsize and body weight are measured twice a week and the study isterminated when the control tumors reach approximately 2000 mm³, and/orif tumor volume exceeds 10% of the animal body weight or if the bodyweight loss exceeds 20%.

The differences in tumor growth trends over time between pairs oftreatment groups are assessed using linear mixed effects regressionmodels. These models account for the fact that each animal is measuredat multiple time points. A separate model is fit for each comparison,and the areas under the curve (AUC) for each treatment group arecalculated using the predicted values from the model. The percentdecrease in AUC (dAUC) relative to the reference group is thencalculated. A statistically significant P value suggests that the trendsover time for the two treatment groups are different.

The tumor measurements observed on a date pre-specified by theresearcher (typically the last day of treatment) are analyzed to assesstumor growth inhibition. For this analysis, a T/C ratio is calculatedfor each animal by dividing the tumor measurement for the given animalby the mean tumor measurement across all control animals. The T/C ratiosacross a treatment group are compared to the T/C ratios of the controlgroup using a two-tailed Welch's t-test. To adjust for multiplicity, aFalse Discovery Rate (FDR) is calculated for each comparison using theapproach described by Benjamini and Hochberg, J.R. Stat. Soc. B 1995,57:289-300.

As detailed above, compounds of the invention inhibit HDAC6. In certainembodiments, compounds of the invention inhibit HDAC6 with an IC₅₀ valueof less than 100 nM including compounds: I-2, I-10, I-17, I-20, I-22,I-28, I-31, I-32, I-35, I-42, I-44, I-47, I-51, I-68, I-75, I-85, I-87,I-89, I-91, I-94, I-99, I-116, I-197, I-240.

In certain embodiments, compounds of the invention inhibit HDAC6 with anIC₅₀ value of greater than 100 nM and less than 1 μM includingcompounds: I-1, I-11, I-12, I-13, I-14, I-21, I-23, I-24, I-29, I-30,I-40, I-45, I-48, I-50, I-52, I-57, I-58, I-60, I-61, I-62, I-65, I-66,I-67, I-70, I-76, I-81, I-92, I-93, I-97, I-100, I-101, I-102, I-103,I-104, I-107, I-110, I-112, I-113, I-114, I-117, I-119, I-120, I-121,I-241.

In certain embodiments, compounds of the invention inhibit HDAC6 with anIC50 value of greater than 1 μM and less than 10 μM including compounds:I-3, I-5, I-6, I-7, I-8, I-15, I-16, I-18, I-26, I-27, I-34, I-37, I-38,I-41, I-46, I-55, I-56, I-59, I-63, I-64, I-72, I-74, I-77, I-79, I-80,I-83, I-88, I-90, I-95, I-96, I-98, I-105, I-106, I-108, I-109, I-115,I-118, I-122, I-123.

In certain embodiments, compounds of the invention inhibit HDAC6 with anIC50 value of greater than 10 μM including compounds: I-4, I-19, I-36,I-53, I-54, I-69, I-71, I-73, I-82, I-84, I-86.

As detailed above, compounds of the invention are selective for HDAC6over other Class I HDAC enzymes. In certain embodiments, the ratio ofHDAC IC50 (as obtained in the nuclear extract assay described above) toHDAC6 IC50 is less than 5 (HDAC IC₅₀/HDAC6 IC₅₀). In certainembodiments, the ratio of HDAC IC₅₀ to HDAC6 IC₅₀ is between 5 and 10.In certain embodiments, the ratio of HDAC IC₅₀ to HDAC6 IC₅₀ is between10 and 100.

While we have described a number of embodiments of this invention, it isapparent that our basic examples may be altered to provide otherembodiments, which utilize the compounds and methods of this invention.Therefore, it will be appreciated that the scope of this invention is tobe defined by the appended claims rather than by the specificembodiments, which have been represented by way of examples.

1. A compound of formula (I):

or a pharmaceutically acceptable salt thereof; wherein: X₁ is CH or N; X₂ is CH or N; n is 1-2; R^(1a) is hydrogen, fluoro, C₁₋₄ alkyl, or C₁₋₃ fluoroalkyl; R^(1b) is hydrogen, fluoro, C₁₋₄ alkyl, or C₁₋₃ fluoroalkyl; or R^(1a) and R^(1b) are taken together to form an oxo group; each occurrence of R^(1c) is independently hydrogen, fluoro, C₁₋₄ alkyl, or C₁₋₃ fluoroalkyl; each occurrence of R^(1d) is independently hydrogen, fluoro, C₁₋₄ alkyl, or C₁₋₃ fluoroalkyl; G is —R³, —V₁—R³, —V₁-L₁-R³, -L₂-V₁—R³, -L₂-V₂—R³, or -L₁-R³; or when R^(1a) and R^(1b) are taken together to form an oxo group, G is —R³, or -L₁-R³; L₁ is an unsubstituted or substituted C₁₋₃ alkylene chain; L₂ is an unsubstituted or substituted C₂₋₃ alkylene chain; V₁ is —C(O)—, —C(S)—, —C(O)—CR^(A)═CR^(A)—, —C(O)—N(R^(4a))—, —C(O)—O—, or —S(O)₂—; V₂ is —N(R^(4a))—, —N(R^(4a))—C(O)—, —SO₂—N(R^(4a))—, —N(R^(4a))—SO₂—, —O—, —S—, —S(O)—, —N(R^(4a))—C(O)—N(R^(4a))—, —N(R^(4a))—C(O)—O—, —O—C(O)—N(R^(4a))—, or —N(R^(4a))—SO₂—N(R^(4a))—; R³ is unsubstituted or substituted C₁₋₆ aliphatic, unsubstituted or substituted 3-10-membered cycloaliphatic, unsubstituted or substituted 4-10-membered heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, unsubstituted or substituted 6-10-membered aryl, or unsubstituted or substituted 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each occurrence of R^(A) is independently hydrogen, fluoro, or unsubstituted or substituted C₁₋₄ aliphatic; and each occurrence of R^(4a) is independently hydrogen, or unsubstituted or substituted C₁₋₄ aliphatic; provided that the compound of formula (I) is other than: N-hydroxy-5-(4-methoxybenzyl)-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2-carboxamide; or N-hydroxy-5-(3-(trifluoromethyl)benzyl)-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2-carboxamide.
 2. The compound of claim 1, wherein: X₁ is CH and X₂ is N; or X₁ is N and X₂ is CH.
 3. The compound of claim 1, wherein n is
 1. 4. The compound of claim 1, wherein: G is —V₁—R³, or —V₁-L₁-R³; and V₁ is —C(O)—.
 5. The compound of claim 1, wherein: R^(1a) is hydrogen, fluoro, or methyl; R^(1b) is hydrogen, fluoro, trifluoromethyl, methyl, ethyl, isopropyl, n-propyl, or tert-butyl; or R^(1a) and R^(1b) are taken together to form an oxo group; each occurrence of R^(1c) is independently hydrogen, fluoro, or methyl; and each occurrence of R^(1d) is independently hydrogen, fluoro, trifluoromethyl, methyl, ethyl, isopropyl, n-propyl, or tert-butyl.
 6. The compound of claim 1, wherein: each substitutable carbon chain atom in R³ is unsubstituted or substituted with 1-2 occurrences of —R^(5dd); each substitutable saturated ring carbon atom in R³ is unsubstituted or substituted with ═O, ═S, ═C(R⁵)₂, ═N—N(R⁴)₂, ═N—OR⁵, ═N—NHC(O)R⁵, ═N—NHCO₂R⁶, ═N—NHSO₂R⁶, ═N—R⁵ or —R^(5a); each substitutable unsaturated ring carbon atom in R³ is unsubstituted or is substituted with —R^(5a); each substitutable ring nitrogen atom in R³ is unsubstituted or substituted with —R^(9b); each R^(5a) is independently halogen, —NO₂, —CN, —C(R⁵)═C(R⁵)₂, —C≡C—R⁵, —OR⁵, —SR⁶, —S(O)R⁶, —SO₂R⁶, —SO₂N(R⁴)₂, —N(R⁴)₂, —NR⁴C(O)R⁵, —NR⁴C(O)N(O)₂, —NR⁴CO₂R⁶, —OC(O)N(R⁴)₂, —C(O)R⁵, —C(O)N(R⁴)₂, —C(═NR⁴)—N(R⁴)₂, —C(═NR⁴)—OR⁵, —N(R⁴)—N(R⁴)₂, —N(R⁴)C(═NR⁴)—N(R⁴)₂, —N(R⁴)SO₂R⁶, —N(R⁴)SO₂N(R⁴)₂, —P(O)(R⁵)₂, —P(O)(OR⁵)₂, unsubstituted or substituted C₁₋₆ aliphatic, unsubstituted or substituted 3-10-membered cycloaliphatic, unsubstituted or substituted 4-10-membered heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, unsubstituted or substituted 6-10-membered aryl, or unsubstituted or substituted 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or two adjacent R^(5a), taken together with the intervening ring atoms, form an unsubstituted or substituted fused aromatic ring or an unsubstituted or substituted non-aromatic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each occurrence of R^(5dd) is independently fluoro, hydroxy, —O(C₁₋₃ alkyl), cyano, —N(R⁴)₂, —C(O)(C₁₋₃ alkyl), —CO₂H, —C(O)NH₂, —N—C(O)—(C₁₋₃ alkyl), —N—C(O)—O—(C₁₋₃ alkyl), or —C(O)NH(C₁₋₃ alkyl). each R⁴ is independently hydrogen, unsubstituted or substituted C₁₋₆ aliphatic, unsubstituted or substituted 3-10-membered cycloaliphatic, unsubstituted or substituted 4-10-membered heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, unsubstituted or substituted 6-10-membered aryl, or unsubstituted or substituted 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or two R⁴ on the same nitrogen atom, taken together with the nitrogen atom, form an unsubstituted or substituted 5- to 6-membered heteroaryl or an unsubstituted or substituted 4- to 8-membered heterocyclyl having, in addition to the nitrogen atom, 0-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur; each R⁵ is independently hydrogen, unsubstituted or substituted C₁₋₆ aliphatic, unsubstituted or substituted 3-10-membered cycloaliphatic, unsubstituted or substituted 4-10-membered heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, unsubstituted or substituted 6-10-membered aryl, or unsubstituted or substituted 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur. each R⁶ is independently unsubstituted or substituted C₁₋₆ aliphatic, or unsubstituted or substituted 6-10-membered aryl; each R^(9b) is independently —C(O)R⁵, —C(O)N(R⁴)₂, —CO₂R⁶, —SO₂R⁶, —SO₂N(R⁴)₂, unsubstituted C₁₋₄ aliphatic, or C₁₋₄ aliphatic substituted with 1-2 occurrences of R⁷ or R⁸; each R⁷ is independently unsubstituted or substituted 4-10-membered heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, unsubstituted or substituted 6-10-membered aryl, or unsubstituted or substituted 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and each R⁸ is independently halogen, —OH, —O(C₁₋₃ alkyl), —CN, —N(R⁴)₂, —C(O)(C₁₋₃ alkyl), —CO₂H, —CO₂(C₁₋₃ alkyl), —C(O)NH₂, or —C(O)NH(C₁₋₃ alkyl).
 7. The compound of claim 6, wherein: each substitutable saturated ring carbon atom in R³ is unsubstituted or substituted with —R^(5a); the total number of R^(5a) substituents is p; p is 1-2; each R^(5a) is independently halogen, cyano, hydroxy, C₁₋₄ alkyl, C₁₋₃ fluoroalkyl, —O—C₁₋₃ alkyl, —O—C₁₋₃ fluoroalkyl, —NHC(O)C₁₋₃ alkyl, —C(O)NHC₁₋₃ alkyl, —NHC(O)NHC₁₋₃ alkyl, —NHS(O)₂C₁₋₃ alkyl, —NHC₁₋₃ alkyl, —N(C₁₋₃ alkyl)₂, 3-10-membered cycloaliphatic substituted with 0-2 occurrences of —R^(7a), 4-10-membered heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur substituted with 0-2 occurrences of —R^(7a), 6-10-membered aryl substituted with 0-2 occurrences of —R^(7a), or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur substituted with 0-2 occurrences of —R^(7a); and each occurrence of R^(7a) is independently halogen, C₁₋₄ alkyl, C₁₋₃ fluoroalkyl, —O—C₁₋₃ alkyl, —O—C₁₋₃ fluoroalkyl, cyano, hydroxy, —NHC(O)C₁₋₃ alkyl, —NHC₁₋₃ alkyl, —N(C₁₋₃ alkyl)₂, —C(O)NHC₁₋₃ alkyl, —NHC(O)NHC₁₋₃ alkyl, or —NHS(O)₂C₁₋₃ alkyl.
 8. The compound of claim 6, represented by formula (I-a):


9. The compound of claim 8, wherein: R^(1a) is hydrogen, fluoro, or methyl; R^(1b) is hydrogen, fluoro, trifluoromethyl, methyl, ethyl, isopropyl, n-propyl, or tert-butyl; or R^(1a) and R^(1b) are taken together to form an oxo group; each occurrence of R^(1c) is independently hydrogen, fluoro, or methyl; and each occurrence of R^(1d) is independently hydrogen, fluoro, trifluoromethyl, methyl, ethyl, isopropyl, n-propyl, or tert-butyl.
 10. The compound of claim 9, wherein R^(1a) and R^(1b) are not taken together to form an oxo group; G is —V₁—R³, or —V₁-L₁-R³; V₁ is —C(O)—; and L₁ is —CH₂—.
 11. The compound of claim 10, wherein: R^(1a) is hydrogen; R^(1b) is hydrogen, fluoro, or methyl; R^(1c) is hydrogen; and each occurrence of R^(1d) is independently hydrogen, fluoro, or methyl.
 12. The compound of claim 9, wherein R^(1a) and R^(1b) are taken together to form an oxo group; and G is —R³, or -L₁-R³.
 13. The compound of claim 12, wherein R^(1c) is hydrogen; and each occurrence of R^(1d) is independently hydrogen, fluoro, or methyl.
 14. The compound of claim 9, wherein: each substitutable saturated ring carbon atom in R³ is unsubstituted or substituted with —R^(+a); the total number of R^(5a) substituents is p; p is 1-2; each R^(5a) is independently halogen, C₁₋₄ alkyl, C₁₋₃ fluoroalkyl, —O—C₁₋₃ alkyl, —O—C₁₋₃-fluoroalkyl, —NHC(O)C₁₋₃ alkyl, —NHC(O)NHC₁₋₃ alkyl, —NHS(O)₂C₁₋₃ alkyl, —NHC₁₋₃ alkyl, —N(C₁₋₃alkyl)₂, 3-10-membered cycloaliphatic substituted with 0-2 occurrences of —R^(7a), 4-10-membered heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur substituted with 0-2 occurrences of —R^(7a), 6-10-membered aryl substituted with 0-2 occurrences of —R^(7a), or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur substituted with 0-2 occurrences of —R^(7a); and each occurrence of R^(7a) is independently halogen, C₁₋₄ alkyl, C₁₋₃ fluoroalkyl, —O—C₁₋₃ alkyl, —O—C₁₋₃ fluoroalkyl, cyano, hydroxy, —NHC(O)C₁₋₃ alkyl, —NHC₁₋₃ alkyl, —N(C₁₋₃alkyl)₂, —C(O)NHC₁₋₃ alkyl, —NHC(O)NHC₁₋₃ alkyl, or —NHS(O)₂C₁₋₃ alkyl.
 15. The compound of claim 6, represented by formula (I-b):


16. The compound of claim 15, wherein: R^(1a) is hydrogen, fluoro, or methyl; R^(1b) is hydrogen, fluoro, trifluoromethyl, methyl, ethyl, isopropyl, n-propyl, or tert-butyl; or R^(1a) and R^(1b) are taken together to form an oxo group; each occurrence of R^(1c) is independently hydrogen, fluoro, or methyl; and each occurrence of R^(1d) is independently hydrogen, fluoro, trifluoromethyl, methyl, ethyl, isopropyl, n-propyl, or tert-butyl.
 17. The compound of claim 16, wherein R^(1a) and R^(1b) are not taken together to form an oxo group; G is —V₁—R³, or —V₁-L₁-R³; V₁ is —C(O)—; and L₁ is —CH₂—.
 18. The compound of claim 17, wherein R^(1a) is hydrogen; R^(1b) is hydrogen, fluoro, or methyl; R^(1c) is hydrogen; and each occurrence of R^(1d) is independently hydrogen, fluoro, or methyl.
 19. The compound of claim 16, wherein R^(1c) and R^(1b) are taken together to form an oxo group; and G is —R³, or -L₁-R³.
 20. The compound of claim 19, wherein: R^(1c) is hydrogen; and each occurrence of R^(1d) is independently hydrogen, fluoro, or methyl.
 21. The compound of claim 16, wherein: each substitutable saturated ring carbon atom in R³ is unsubstituted or substituted with —R^(+a); the total number of R^(5a) substituents is p; p is 1-2; each R^(5a) is independently halogen, C₁₋₄ alkyl, C₁₋₃ fluoroalkyl, —O—C₁₋₃ alkyl, —O—C₁₋₃-fluoroalkyl, —NHC(O)C₁₋₃ alkyl, —NHC(O)NHC₁₋₃ alkyl, —NHS(O)₂C₁₋₃ alkyl, —NHC₁₋₃ alkyl, —N(C₁₋₃alkyl)₂, 3-10-membered cycloaliphatic substituted with 0-2 occurrences of —R^(7a), 4-10-membered heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur substituted with 0-2 occurrences of —R^(7a), 6-10-membered aryl substituted with 0-2 occurrences of —R^(7a), or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur substituted with 0-2 occurrences of —R^(7a); and each occurrence of R^(7a) is independently halogen, C₁₋₄ alkyl, C₁₋₃-fluoroalkyl, —O—C₁₋₃ alkyl, —O—C₁₋₃-fluoroalkyl, cyano, hydroxy, —NHC(O)C₁₋₃ alkyl, —NHC₁₋₃ alkyl, —N(C₁₋₃alkyl)₂, —C(O)NHC₁₋₃ alkyl, —NHC(O)NHC₁₋₃ alkyl, or —NHS(O)₂C₁₋₃ alkyl.
 22. The compound of claim 6, represented by formula (I-c):


23. The compound of claim 22, wherein: R^(1a) is hydrogen, fluoro, or methyl; R^(1b) is hydrogen, fluoro, trifluoromethyl, methyl, ethyl, isopropyl, n-propyl, or tert-butyl; or R^(1a) and R^(1b) are taken together to form an oxo group; each occurrence of R^(1c) is independently hydrogen, fluoro, or methyl; and each occurrence of R^(1d) is independently hydrogen, fluoro, trifluoromethyl, methyl, ethyl, isopropyl, n-propyl, or tert-butyl.
 24. The compound of claim 23, wherein R^(1a) and R^(1b) are not taken together to form an oxo group; G is —V₁—R³, or —V₁-L₁-R³; V₁ is —C(O)—; and L₁ is —CH₂—.
 25. The compound of claim 24, wherein R^(1a) is hydrogen; R^(1b) is hydrogen, fluoro, or methyl; R^(1c) is hydrogen; and each occurrence of R^(1d) is independently hydrogen, fluoro, or methyl.
 26. The compound of claim 23, wherein R^(1a) and R^(1b) are taken together to form an oxo group; and G is —R³, or -L₁-R³.
 27. The compound of claim 26, wherein: R^(1c) is hydrogen; and each occurrence of R^(1d) is independently hydrogen, fluoro, or methyl.
 28. The compound of claim 23, wherein: each substitutable saturated ring carbon atom in R³ is unsubstituted or substituted with —R^(5a); the total number of R^(5a) substituents is p; p is 1-2; each R^(5a) is independently halogen, C₁₋₄ alkyl, C₁₋₃ fluoroalkyl, —O—C₁₋₃ alkyl, —O—C₁₋₃ fluoroalkyl, —NHC(O)C₁₋₃ alkyl, —NHC(O)NHC₁₋₃alkyl, —NHS(O)₂C₁₋₃ alkyl, —NHC₁₋₃ alkyl, —N(C₁₋₃alkyl)₂, 3-10-membered cycloaliphatic substituted with 0-2 occurrences of —R^(7a), 4-10-membered heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur substituted with 0-2 occurrences of —R^(7a), 6-10-membered aryl substituted with 0-2 occurrences of —R^(a), or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur substituted with 0-2 occurrences of —R^(7a); and each occurrence of R^(7a) is independently halogen, C₁₋₄ alkyl, C₁₋₃-fluoroalkyl, —O—C₁₋₃ alkyl, —O—C₁₋₃-fluoroalkyl, cyano, hydroxy, —NHC(O)C₁₋₃ alkyl, —NHC₁₋₃ alkyl, —N(C₁₋₃alkyl)₂, —C(O)NHC₁₋₃ alkyl, —NHC(O)NHC₁₋₃ alkyl, or —NHS(O)₂C₁₋₃ alkyl.
 29. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier.
 30. A method of treating a proliferative disorder in a patient comprising administering to said patient a therapeutically effective amount of a compound of claim
 1. 31. The method of claim 30, wherein the proliferative disorder is breast cancer, lung cancer, ovarian cancer, multiple myeloma, acute myelogenous leukemia, or acute lymphoblastic leukemia.
 32. A method for inhibiting HDAC6 activity in a patient comprising administering a pharmaceutical composition comprising an amount of a compound of claim 1 effective to inhibit HDAC6 activity in the patient. 